7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid and the process for the preparation thereof

ABSTRACT

The present invention relates to a novel quinolone compound having an excellent antibacterial activity. More specifically, the present invention relates to 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid represent by the following formula: or its isomer.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of Ser. No. 09/049,024, filed Mar.27, 1998, which is a divisional of Ser. No. 08/825,992, filed Apr. 4,1997, now U.S. Pat. No. 5,776,944, which is a continuation-in-part ofSer. No. 08/490,978 filed Jun. 15, 1995, now U.S. Pat. No. 5,633,262.

BACKGROUND OF INVENTION

1. Field of Invention

The present invention relates to a novel quinoline(naphthyridine)carboxylic acid derivative having an excellent antibacterial activity.More specifically, the present invention relates to a novelquinoline(naphthyridine)carboxylic acid derivative represented by thefollowing formula (I), which has an 4-aminomethyl-3-oximepyrrolidinesubstituent on 7-position of the quinolone nucleus and shows a superiorantibacterial activity in contrast to the known quinolone antibacterialagents and also has a broad antibacterial spectrum and a highly improvedpharmacokinetic property: ##STR2## and its pharmaceutically acceptablenon-toxic salt, its physiologically hydrolyzable ester, solvate andisomer, in which

R represents hydrogen, methyl or amino;

Q represents C--H, C--F, C--Cl, C--OH, C--CH₃, C--O--CH₃ or N;

R₁ represents cyclopropyl, ethyl, or phenyl which is substituted withone or more fluorine atom(s);

R₂ represents one of the following a) through e):

a) hydrogen, straight or branched C₁ -C₄ alkyl, cyclopropyl,cyclopropylmethyl, C₃ -C₆ alkynyl, 2-haloethyl, methoxymethyl,methoxycarbonylmethyl, aryl or allyl,

b) a group of the following formula (1), ##STR3## wherein X representshydrogen, 2, 3 or 4-fluoro, cyano, nitro, methoxy, C₁ -C₄ alkyl, or2,4-difluoro,

c) a group of the following formula (2), ##STR4## d) a heteroarylmethylof the following formula (3), ##STR5## e) a group of the followingformula (4), ##STR6## wherein n denotes 0 or 1, m denotes 0, 1 or 2, andX represents methylene, O or N, and

R₃ and R₄ independently of one another represent hydrogen or C₁ -C₃alkyl or R₃ and R₄ together with a nitrogen atom to which they areattached can form a ring.

The present invention also relates to a process for preparing thecompound of formula (I), as defined above, and an antibacterialcomposition comprising the compound of formula (I) as an activecomponent.

2. Background Art

Since in 1962 nalidixic acid was first introduced as an agent fortreating urinary tract infection (see, G. Y. Lesher, et al., J. Med.Chem. 5, 1063-1065 (1962)), numerous quinoline carboxylic acidantibacterial agents, including oxolinic acid, rosoxacin, pipemidicacid, etc., have been developed. However, these early-stage antibaterialagents have a little activity against gram-positive bacterial strainsand thus have been used only against gram-negative strains.

Recently, norfloxacin which is the quinolone compound having a fluorineon 6-position has been newly developed (see, H. Koga, et al., J. Med.Chem., 23, 1358-1363 (1980)), and thereafter an extensive study todevelop various quinolone antabacterial compounds has been conducted.However, since norfloxacin has a weak antibacterial activity againstgram-positive strains and shows poor distribution and absorption inliving body, it has been used only for treatment of diseases includingurinary tract infections, gastro-intestinal infections, sexuallytransmitted diseases and the like. Thereafter, ciprofloxacin (see, R.Wise, et al., J. Antimicrob. Agents Chemother., 23, 559 (1983)),ofloxacin (see, K. Sata, et al., Antimicrob. Agents Chemother., 22, 548(1982)) and the like have been developed. These antibacterial agentshave a superior and broad antibacterial activity in comparison with theearly-stage antibacterial compounds, and therefore, have been widely andpractically used for treatment of diseases in clinical field.

The compounds in use or under clinical test include mainly thederivatives having a piperazine substituent on 7-position of thequinolone nucleus as in ciprofloxacin or ofloxacin. However, as a resultof the study to develop quinolone compounds having a more potent andbroad antibacterial activity it has been disclosed that a compoundhaving an 3-amino or 3-aminomethylpyrroidine group introduced into7-position has an increased activity against gram-positive strains, incomparison with the compounds having 7-piperazine group, whilemaintaining a potent activity against gram-negative strains. However,unfortunately, the compounds having pyrrolidine substituent have a lowsolubility in water in comparison with the compounds having piperazinesubstituent, and thus their in-vivo antibacterial activity is not sohigh as the in-vitro activity. Accordingly, numerous study has beencontinuously conducted to improve the disadvantage of the compoundshaving pyrrolidine substituent, that is, to increase the solubility inwater and to improve the pharmacokinetic property.

As a result, many reports of such study have been made. For example, ithas been disclosed that ((2S,4S)-4-amino-2-methylpyrrolidinyl)naphthyridine derivatives (see, Rosen,T., Chu, D. T. W. etc. J. Med. Chem. 1988, 31, 1598-1611) or(trans-3-amino-4-methylpyrrolidinyl)naphthyridine derivatives (see,Matsumoto, J. et al., Proceedings of the 14th International Congress ofChemotherapy; Ishigami, J., Ed.; University of Tokyo Press: Tokyo, 1985;pp 1519-1520) shows a 20 to 40 times increase in water-solubility, anincreased bioavailability and an improved pharmacokinetic property, incomparison with the compounds having no methyl group, with a similarin-vitro antibacterial activity.

In addition, an attempt to improve the disadvantage of the priorquinolone compounds including a relatively low antibacterial activityagainst gram-positive strains, a low water-solubility and a poorpharmacokinetic property has been made by introducing differentfunctional groups, instead of amino group, into the pyrrolidine orpiperazine moiety. As one of such attempt, some compounds having anoxime group introduced into the 7-amine moiety of quinolone compoundshave been reported. For example, the researchers of Abbott have reportedin a scientific journal, J. Med. Chem., 1992, 35, 1392-1398, that thequinolone compound having the following general formula A! wherein3-oxime(or methyloxime)pyrrolidine group or 4-oxime(ormethyloxime)piperidine group is substituted on 7-position of quinolonenucleus exhibits a good antibacterial activity against gram-positivestrains: ##STR7## in which R represents cyclopropyl or2,4-difluorophenyl;

R' represents hydrogen or methyl;

X represents C--H, C--F or N; and

n denotes 1 or 2.

The compound A! has some disadvantages that it shows a goodantibacterial activity against gram-positive strains but a relativelyweak activity against gram-negative strains, and also has a relativelylow antibacteral activity in in-vivo test.

In addition, Japanese Laid-open Patent Publication No. (Hei) 01-100165(1989) discloses the compound having the following general formula B!:##STR8## in which R represents cyclopropyl, 2,4-difluorophenyl or4-hydroxyphenyl;

X represents C--H, C--F or C--Cl; and

R' represents oxime or hydroxyaminopyrrolidine-derived substituent.

Specifically, in said Japanese laid-open publication the oxime orhydroxyaminopyrrolidine-derived groups as R' substituent are verybroadly disclosed. However, only the 3-hydroxyaminopyrrolidine thefollowing formula (a)!, 3-methoxyaminopyrrolidine the following formula(b)!, 3-amino-4-methoxyaminopyrrolidine the following formula (c)!,3-oximepyrrolidine the following formula (d)! and3-methyloximepyrrolidine the following formula (e)! groups arespecifically exemplified but the pyrrolidine substituent having both3-oxime and 4-aminomethyl groups has never been specifically mentioned.##STR9##

Further, European Early Patent Publication No. 0 541 086 discloses thequinolone compound having the following general formula C!: ##STR10## inwhich R and R₁ independently of one another represent hydrogen or C₁ -C₅alkyl;

R₂ represents hydrogen, amino, fluoro or hydroxy;

R₃ represents C₃ -C₇ cycloalkyl;

R₄ represents methoxy or fluoro;

R₅ and R₆ can be identical with or different from each other andindependently of one another represent hydrogen or alkyl, or R₅ and R₆together can form C₃ -C₅ cycloalkyl;

m denotes 0 or 1; and

n denotes an integer of 1 to 3.

Among the compounds C! disclosed in said European early patentpublication the typical substituent on 7-position of quinolone nucleusis a group having the following structure: ##STR11##

However, the compound of formula C! does not include any compound havingboth oxime group and aminomethyl group on 7-position, and therefore, isdifferent from the compound of the present invention.

The common characteristic feature of the known oxime orhydroxyamine-derived compounds as mentioned above is that they exhibit agood activity against gram-positive strains including MRSA (MethicillinResistant Staphylococcus aureus) strains in comparison with the earlydeveloped quinolone compounds but show a weak activity againstgram-negative strains in comparison with the antibacterial agentsincluding ofloxacin or ciprofloxacin. Therefore, it can be said thattheir antibacterial spectrum may be narrower than that of the knownofloxacin or ciprofloxacin antibacterial compound.

Thus, on the basis of prior art as mentioned above the present inventorshave extensively studied to develop the novel oxime-aminomethylcompound, which shows a potent antibacterial activity against broadspectrum pathogenic strains including resistant strains and alsoexhibits more improved pharmacokinetic properties and high absorption inliving body, by introducing various substituted pyrrolidine groups into7-position of quinoline nucleus and determining pharmacologicalactivities of the resulting compounds. As a result, we have identifiedthat the quinolone compounds having the general formula (I), as definedabove, wherein 4-aminomethyl-3-(optionally substituted)oxime-pyrrolidinegroup is introduced into 7-position of quinoline nucleus can satisfysuch purpose, and thus completed the present invention.

Therefore, it is an object of the present invention to provide a novelquinoline(naphthyridine) carboxylic acid derivative of formula (I), asdefined above, which shows a potent antibacterial activity against broadpathogenic strains including both gram-positive and gram-negativestrains and also has a good pharmacokinetic property.

It is another object of the present invention to provide a process forpreparing the novel quinoline(naphthyridine) carboxylic acid derivativeof formula (I).

It is a further object of the present invention to provide anantibacterial composition comprising the novel quinoline(naphthyridine)carboxylic acid derivative of formula (I) as an activecomponent.

BRIEF DESCRIPTION OF THE DRAWINGS

For a thorough understanding of the nature and objects of the invention,reference should be made to the following detailed description taken inconnection with the accompanying drawings in which:

FIG. 1 represents the moisture adsorption velocity profile of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate at 25° C.;

FIG. 2 represents the isothermal moisture adsorption profile of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate at 25° C.;

FIG. 3 represents the equilibrium moisture content of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.3 hydrate at a relative humidity of 23 to 75%;

FIG. 4 represents test result on moisture adsorption of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.1.5 hydrate;

FIG. 5 represents the powder X-ray diffraction pattern of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate anhydride;

FIG. 6 represents the powder X-ray diffraction pattern of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.3 hydrate;

FIG. 7 represents the powder X-ray diffraction pattern of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.1.5 hydrate;

FIG. 8 represents the variation in moisture content with elapsed time of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate anhydride taken after 0, 5, 10, 20, 30, and 60minutes, respectively, from the initial point while being passed throughwith humidified nitrogen;

FIG. 9 represents the results of Differential Scanning Calorimetry on7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate anhydride and 3 hydrate;

FIG. 10 represents the results of thermogravimetric analysis on7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.3 hydrate.

DISCLOSURE OF INVENTION

In one aspect, the present invention relates to a novelquinoline(naphthyridine) carboxylic acid derivative having the followingformula (I): ##STR12## and its pharmaceutically acceptable non-toxicsalt, its physiologically hydrolyzable ester, solvate and isomer, inwhich

R represents hydrogen, methyl or amino;

Q represents C--H, C--F, C--Cl, C--OH, C--CH₃, C--O--CH₃ or N;

R₁ represents cyclopropyl, ethyl, or phenyl which is substituted withone or more fluorine atom(s);

R₂ represents one of the following a) through e):

a) hydrogen, straight or branched C₁ -C₄ alkyl, cyclopropyl,cyclopropylmethyl, C₃ -C₆ alkynyl, 2-haloethyl, methoxymethyl,methoxycarbonylmethyl, aryl or allyl,

b) a group of the following formula (1), ##STR13## wherein X representshydrogen, 2, 3 or 4-fluoro, cyano, nitro, methoxy, C₁ -C₄ alkyl, or2,4-difluoro,

c) a group of the following formula (2), ##STR14## d) a heteroarylmethylof the following formula (3), ##STR15## e) a group of the followingformula (4), ##STR16## wherein n denotes 0 or 1, m denotes 0, 1 or 2,and X represents methylene, O or N, and

R₃ and R₄ independently of one another represent hydrogen or C₁ -C₃alkyl or R₃ and R₄ together with a nitrogen atom to which they areattached can form a ring.

Among the compound of formula (I), as defined above, having a superiorantibacterial activity, a broad antibacterial spectrum and an excellentpharmacokinetic property, the preferred compounds include those whereinQ represents C--H, C--F, C--Cl, C--OMe or N, R represents hydrogen oramino, R₁ represents cyclopropyl or 2,4-difluorophenyl, R₂ representshydrogen, methyl, ethyl, isopropyl, t-butyl, phenyl, propargyl,homopropargyl, 2-fluoroethyl, benzyl, 2-fluorobenzyl or 2-cyanobenzyl,and R₃ and R₄ represent hydrogen.

More preferred compounds of formula (I) include those wherein Qrepresents C--H, C--Cl, C--F or N, R represents hydrogen or amino, R₁represents cyclopropyl, R₂ represents methyl, t-butyl, homopropargyl,2-fluoroethyl, benzyl or 2-fluorobenzyl, and R₃ and R₄ representhydrogen.

In the pyrrolidine moiety of the compound of formula (I) the 4-carbonatom on which aminomethyl group is substituted is an assymetric carbonatom and thus can be present in the form of R or S or a mixture of R abdS. In addition, due to the presence of (optionally substituted) oximegroup on 3-position of pyrrolidine moiety the compound of formula (I)can be present in the form of syn- and anti-isomers depending on theirgeometric structure. Thus, the present invention also includes all ofthose geometric isomers and their mixtures.

The compound of formula (I) according to the present invention can forma pharmaceutically acceptable non-toxic salt. Such salt includes a saltwith inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid, etc., a salt with organic carboxylicacids such as acetic acid, trifluoroacetic acid, citric acid, maleicacid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaricacid, mandelic acid, ascorbic acid or malic acid or with sulfonic acidssuch as methanesulfonic acid, para-toluenesulfonic acid, etc., and asalt with other acids which are generally known and conventionally usedin the technical field of quinolone-based compounds. These acid-additionsalts can be prepared according to a conventional conversion method.

Particularly, the present invention relates to the7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate and its hydrate represented by the followingformula (H), ##STR17## in which n denotes 0, 1, 1.5, 2, 2.5, 3, 3.5 or4, having an improved bioavailability.

The methanesulfonate and its hydrate as defined above exhibit the samepotent antibacterial activity as the free form, also have desirablephysicochemical properties such as excellent solubility, constantmoisture content, etc. regardless of the ambient relative humidity.

Gererally, conversion of a pharmacologically active compound into a saltform induces a change in the compound's physicochemical properties suchas solubility, absorption velocity, etc. Therefore, study about aneffective salt form for developing a successful new medicine has beenconventionally made. Pharmaceutically more desirable crystal form may beselected by studying whether or not any pseudopolymorph can be producedand its physicochemical properties (see, Remington's Pharmaceutics,Chapter 75 Preformulation; Byrn, S. R. Solid Chemistry of Drugs,Academic Press, New York, 1982). The hydrate, one such pseudopolymorph,has water molecules inside the crystal, and thus has a crystallinestructure different from that of the anhydride, as can be verified fromtheir respective X-ray diffraction patterns. A pseudopolymorph differsfrom the original compound not in its chemical properties, such aspharmacological activity, but in its physical properties, such ascrystallinity, hygroscopicity, melting point, solubility, solubilizingvelocity, etc. So, the pseudopolymorph has been recognized aspharmaceutically important (see, Morris, K. P. et al., Int. J. Pharm.,108, 15-206 (1994)).

In the process of identifying the physicochemical properties ofmethanesulfonate, the salt has been found to exist as a stable hydratewhen the number of water molecules contained in one molecule varieswithin a specific range. Here, stability does not mean chemicalstability but the difficulty of recoving water molecules. That is, astable hydrate neither loses the water molecules contained therein norabsorbs moisture over a wide range of ambient relative humidity. Incontrast, moisture absorption by the anhydride varies greatly with theambient relative humidity. As a result of experiments carried out by thepresent inventors,7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate has been shown to exist as a stable hydrate forvalues of the hydration number n equal only to 1, 1.5, 2, 2.5, 3, 3.5 or4. Among these, 3 is preferred, since the change of moisture content islowest at that hydration number.

The moisture content of the hydrate varies with the hydration number (n)of the hydrated molecule. Since the molecular weight of7-(4-amino-methyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate is 485.5, the moisture content of the hydrate forn equal to 1, 1.5, 2, 2.5, 3, 3.5 or 4 is calculated to be 3.6%, 5%,6.9%, 8.5%, 10.0%, 11.5% or 12.9%, respectively. However, the actualmoisture content may differ from the calculated moisture contentdepending on differences in recrystallization conditions, dryingconditions, etc. The range of the actual moisture content for eachhydration number is shown in the following Table A.

                  TABLE A    ______________________________________    Moisture Content according to Hydration Number    Hydration Number (n)                    Moisture Content (%)    ______________________________________    1               2-4    1.5             4-6    2               6-8    2.5             8-9    3                9-11    3.5             11-12    4               12-13    ______________________________________

If two or more hydrates having different moisture contents are mixedtogether, mixtures having a new moisture content by weight, for example,a mixture of 1 hydrate and 1.5 hydrate having a moisture content of 2 to6%; a mixture of 1.5 hydrate and 2 hydrate having a moisture content of4 to 8%; a mixture of 2 hydrate and 2.5 hydrate having a moisturecontent of 6 to 9%; a mixture of 2.5 hydrate and 3 hydrate having amoisture content of 8 to 11%; a mixture of 3 hydrate and 3.5 hydratehaving a moisture content of 9 to 12%; or a mixture of 3.5 hydrate and 4hydrate having a moisture content of 11 to 13%, can be obtained.

It has also been found that the relative humidity range at which themoisture content of each hydrate can be maintained constant differ fromeach other. That is, although the 3 hydrate has a constant moisturecontent at a relative humidity of 23 to 1.5 hydrate is constant at arelative humidity of 23 to 64% only (see, FIGS. 3 and 4).

In the second aspect, the present invention also relates to a processfor preparing the novel compound of formula (I).

According to the present invention, the compound of formula (I) can beprepared by reacting a compound of formula (II) with a compound offormula (III) or a salt thereof, as shown in the following reactionscheme 1. ##STR18## In the above scheme, R, R₁, R₂, R₃, R₄ and Q aredefined as previously described; and

X represents a halogen atom, preferably chlorine, bromine or fluorine.

According to the above reaction scheme 1, the compound of formula (I)according to the present invention can be prepared by stirring thecompound of formula (II) and the compound of formula (III) in thepresence of a solvent for 1 to 20 hours at the temperature between roomtemperature and 200° C. with the addition of a suitable base. In thisreaction, the compound of formula (III) can be used in the form of afree compound or a salt with an acid such as hydrochloric acid,hydrobromic acid or trifluoroacetic acid.

As the solvent for the above reaction, any solvent which does notadversely affect the reaction can be used. Preferably, acetonitrile,dimethylformamide(DMF), dimethylsulfoxide(DMSO), pyridine,hexamethylphosphoramide(HMPA), N-methylpyrrolidinone, ethanol, andaqueous mixtures thereof can be used.

This reaction is generally conducted in the presence of an acidacceptor. In this case, to increase the reaction efficiency of therelatively expensive starting material (II) the reactant (III) is usedin an excessive amount, for example, an equimolar amount to 10 timesmolar amount, preferably an equimolar amount to 5 times molar amount,with respect to the starting material (II). When the reactant (III) isused in an excessive amount, the unreacted compound of formula (III)which is retained after the reaction can he recoverd and reused inanother reaction. The acid acceptor which can be preferably used in thisreaction includes inorganic bases such as sodium hydrogen carbonate,potassium carbonate, etc., and organic bases such as triethylamine,diisopropylethylamine, pyridine, N,N-dimethylaniline,N,N-dimethylaminopyridine, 1,8-diazabicyclo 5.4.0!undec-7-ene(DBU),1,4-diazabicyclo 2.2.2!octane(DABCO), etc.

The compound of formula (I) according to the present invention can alsoprepared by a method depicted in the following reaction scheme 2, inwhich a protecting group P is introduced into one of R₃ and R₄ of thecompound of formula (III) wherein R₃ and R₄ are hydrogen to prepare thecompound of formula (III') wherein the amino group is protected with P,the protected compound of formula (III') is reacted with the compound offormula (II) under the same condition as in the reaction scheme 1, andthen the resulting compound of formula (I') is deprotected by removingthe protecting group P to form the desired compound of formula (I).##STR19## in the above reaction scheme, R, R₁, R₂ and Q are defined aspreviously described; and

P represents an amino-protecting group.

In the reaction of the above reaction scheme 2, the compound of formula(III') can be used in the form of a free compound or a salt withhydrochloric acid, hydrobromic acid or trifluoroacetic acid, as in thecompound of formula (III) used in the reaction scheme 1.

Any protecting group which is conventionally used in the field oforganic chemistry and can be readily removed after the reaction withoutdecomposition of the structure of the desired compound can be used asthe suitable amino-protecting group P in the compound of formula (III').The specific example of protecting groups which can be used for thispurpose includes formyl, acetyl, trifluoroacetyl, benzoyl,para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, para-methoxybenzyloxycarbonyl,trichloroethoxycarbonyl, beta-iodoethoxycarbonyl, benzyl,para-methoxybenzyl, trityl, tetrahydropyranyl, para-nitrobenzoyl, etc.

After the reaction is completed, the amino-protecting group present inthe resulting compound of formula (I') can be removed by hydrolysis,solvolysis or reduction depending on properties of the relevantprotecting group. For example, the compound of formula (I') is treatedin a solvent in the presence or absence of an acid or base at thetemperature of 0 to 130° C. to remove the protecting group. As the acidwhich can be used for this purpose, an inorganic acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,etc., an organic acid such as acetic acid, trifluoroacetic acid, formicacid, toluenesulfonic acid, etc., or a Lewis acid such as borontribromide, aluminum chloride, etc., can be mentioned. As the base forthis purpose, hydroxide of an alkali or alkaline earth metal such assodium hydroxide, barium hydroxide, etc., an alkali metal carbonate suchas sodium carbonate, calcium carbonate, etc., an alkali metal alkoxidesuch as sodium methoxide, sodium ethoxide, etc., or sodium acetate, andthe like can be used. The reaction can be carried out in the presence ofa solvent, for example, water or an organic solvent such as ethanol,tetrahydrofuran, dioxane, ethyleneglycol, acetic acid, etc., or amixture of such organic solvent and water. If required, this reactioncan also be practiced in the absence of any solvent.

In addition, when the protecting group is para-toluenesulfonyl, benzyl,trityl, para-methoxybenzyl, benzyloxycarbonyl,para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl,beta-iodoethoxycarbonyl and the like, such groups can be effectivelyremoved by means of a reduction. Although the reaction condition of thereduction for removing protecting group may be varied with properties ofthe relevant protecting group, the reduction can be generally carriedout with hydrogen gas stream in an inert solvent in the presence of acatalyst such as platinum, palladium, Raney nickel, etc., at thetemperature of 10 to 100° C. or with metal sodium or metal lithium inammonia at the temperature of -50 to -10° C.

The compound of formula (II) used as the starting material in thepresent invention is a known compound and can be readily preparedaccording to a method known in the prior publication (see, J. M.Domagala, et al., J. Med. Chem. 34, 1142 (1991); J. M. Domagala, et al.,J. Med. Chem 31, 991 (1988); D. Bouzard, et al., J. Med. Chem. 35, 518(1992)).

The compound of formula (III) used as another starting material in thepresent invention can be readily prepared according to the method asdepicted in the following reaction schemes 3, 4 and 5. ##STR20## In theabove reaction schemes 3 and 4,

the protecting groups P and P' independently of one another representthe same amino-protecting group as defined for P in connection with thecompound of formula (III') and can be identical with or different fromeach other; and

Py represents pyridine.

The process depicted in the reaction schemes 3 and 4 will bespecifically explained hereinafter.

According to the reaction scheme 3, first a cyano ester 1! having aprotected amino group can be reacted with sodium ethoxide in a solventsuch as ethanol to obtain a 3-keto-4-cyanopyrrolidine 2!. The resultingcyanopyrrolidine 2! is reduced with hydrogen gas in the presence of aplatinum catalyst to prepare an aminoalcohol 3!. In this case, thecyanopyrrolidine 2! may be reduced by means of other reductant toprepare the aminoalcohol 3!. For example, the ketone and cyano groupscan be reduced with lithium aluminumhydride(LAH), sodiumborohydride-cobalt chloride complex(NaBH₄ --CoCl₃) or lithiumborohydride(LiBH₄). Alternatively, the aminialcohol 3! can besynthesized by reducing first the ketone group to a hydroxyl group bymeans of sodium borohydride(NaBH₄) and then reducing the cyano group bylithium aluminum hydride(LAH). Then, the amino group of the aminoalcohol3! thus prepared is selectively protected to obtain a protected amine4!, which is then treated with sulfur trioxide(SO₃)-pyridine mixture indimethylsulfoxide solvent (see, Parikh, J. R. and Doering, W. v. E. J.Am. Chem. Soc. 1967, 89, 5505), or oxidized with other oxidant, toprepare a ketone compound 5!. The resulting ketone compound 5! is thenreacted with a O-substituted hydroxyamine of formula R₂ ONH₂ to obtainthe desired substituted oxime compound 6!, which can be deprotected bymeans of a suitable method selected depending on the kind of protectinggroup to obtain the desired oxime compound (III) wherein R₃ and R₄ arehydrogen, i.e. the compound of formula (III-a).

Alternatively, according to the method depicted in the reaction scheme4, the ketone compound 5! is reacted with hydroxyamine to obtain thedesired oxime compound 7! and the compound 7! is reacted with a suitableelectrophilic compound of formula R₂ X which can introduce the desiredR₂ group, in the presence of a base to prepare the oxime derivative offormula 6!, which is then deprotected by means of a suitable methodselected depending on the kind of protecting group in the same manner asin the reaction scheme 3 to prepare the desired oxime compound (III-a).

The compound of formula (III) wherein R₃ and R₄ of aminomethyl grouppresent on 4-position of pyrrolidine are other than hydrogen, i.e. thecompound of formula (III-b), can be prepared by the following reactionscheme 5. ##STR21## In the above reaction scheme, R₃ ' and R₄ 'represent the same meaning as defined for R₃ and R₄ in connection withthe compound of formula (I), provided that they cannot be hydrogen.

According to the method of reaction scheme 5, first the amine compound3! is treated with C₁ -C₃ aldehyde and then reduced to obtain asubstituted amine compound 8! and the resulting amine compound 8! istreated with sulfur trioxide(SO₃)-pyridine mixture in dimethylsulfoxidesolvent, or oxidized with other oxidant, to obtain a ketone compound 9!.The resulting ketone compound 9! can be treated in the same manner as inthe method for treating ketone compound 5! in the reaction schemes 3 and4 to synthesize the desired compound of formula (III-b).

The7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate can be prepared by adding the methanesulfonic acidto the corresponding quinolone carboxylic acid compound in an amount of0.95 to 1.5 times molar amount with respect to the quinolone carboxylicacid compound, or by adding the same amount of the methanesulfonic acidwhich is already dissolved in a solvent to the quinolone carboxylic acidcompound. Although solvents suitable for the above preparation includeC₁ -C₄ haloalkanes, C₁ -C₈ alcohols and water, a solvent selected fromthe group consisting of dichloromethane, chloroform, 1,2-dichloroethane,methanol, ethanol, propanol, and water is preferred. If necessary, thequinolone carboxylic acid compound in a solvent may be heated todissolve the former before the methanesulfonic acid is added. If thequinolone carboxylic acid compound-solution exists as a suspension, acidmay be added to the suspension to obtain a thoroughly transparentsolution. The resulting reaction mixture is stirred for 1 to 24 hours ata temperature of -10 to 40° C. or is allowed to stand, then the productis obtained as a solid according as the solubility of the productdecreases. The methanesulfonate can also be obtained in a high yield byremoving the solvent used under reduced pressure.

The hydrates of the methanesulfonate of the present invention may easilybe prepared by means of conventional methods well known in the art towhich the present invention pertains. Particularly, the differenthydrates may be prepared merely by changing recrystallizationconditions.

The synthetic methods as described above will be more specificallyexplained in the following preparation examples.

The present invention also provides an antibacterial compositioncomprising the novel compound of formula (I), as defined above, or apharmaceutically acceptable salt thereof as an active component togetherwith a pharmaceutically acceptable carrier. When such antibacterialcomposition is used for clinical purpose, it may be formulated intosolid, semi-solid or liquid pharmaceutical preparations for oral,parenteral or topical administration by combining the compound offormula (I) with a pharmaceutically acceptable inert carrier. Thepharmaceutically acceptable inert carrier which can be used for thispurpose may be solid or liquid. The solid or semi-solid pharmaceuticalpreparation in the form of powders, tablets, dispersible powders,capsules, cachets, suppositories and ointments may be prepared in whichcase solid carriers are usually used. The solid carrier which can beused is preferably one or more substances selected from the groupconsisting of diluents, flavouring agents, solubilizing agents,lubricants, suspending agents, binders, swelling agents, etc. or may beencapsulating substances. In the case of powder preparation, themicronized active component is contained in an amount of 5 or 10 to 70%in the carrier. Specific example of the suitable solid carrier includesmagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectine,dextrin, starch, gelatin, tragaganth, methylcellulose, sodiumcarboxymethylcellulose, low boiling wax, cocoa butter, etc. Because oftheir ease in administration, tablets, powders, cachets and capsulesrepresent the most advantageous solid preparation for oraladministration.

The liquid preparation includes solutions, suspensions and emulsions.For example, the injectable preparation for parenteral administrationmay be in the form of water or water-propyleneglycol solution, of whichisotonicity, pH and the like can be adjusted to be suited for thephysiological condition of living body. The liquid preparation can alsobe prepared in the form of a solution in aqueous polyethyleneglycolsolution. The aqueous solution for oral administration can be preparedby dissolving the active component in water and adding a suitablecoloring agent, flavouring agent, stabilizer and thickening agentthereto The aqueous suspension suitable for oral administration can beprepared by dispersing the micronized active component in viscoussubstances such as natural or synthetic gum, methylcellulose, sodiumcarboxymethylcellulose and other known suspending agent.

It is especially advantageous to formulate the aforementionedpharmaceutical preparations in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit forms of thepreparation refer to physically discrete units suitable as unitarydosage, each unit containing a predetermined quantity of the activecomponent calculated to produce the desired therapeutic effect. Suchdosage unit form can be in the packaged form, for example, a tablet, acapsule or a powder filled in vial or ampule, or an ointment, gel orcream filled in tube or bottle.

Although the amount of the active component contained in the dosage unitform can be varied, it can be generally adjusted within the range of 1to 100 mg depending on the efficacy of the selected active component.

When the active compound of formula (I) of the present invention is usedas a medicine for treatment of bacterial infections, it is preferablyadministered in an amount of about 6 to 14 mg per kg of body weight atthe first stage. However, the administration dosage can be varied withthe requirement of the subject patient, severity of the infections to betreated, the selected compound and the like.

The preferred dosage suitable for a certain condition can be determinedby a person skilled in this art according to a conventional manner. Ingeneral, the therapeutic treatment is started from the amount less thanthe optimal dosage of the active compound and then the administrationdosage is increased little by little until the optimal therapeuticeffect is obtained. As a matter of convenience, the total daily dosagecan be divided into several portions and administered over severaltimes.

As mentioned above, the compound of the present invention shows a potentand broad spectrum antibacterial activity against various pathogenicorganisms including gram-positive and gram-negative strains. Theantibacterial activity of the present compound against gram-negativestrains is comparable to or higher than that of the known antibacterialagents (for example, ciprofloxacin), and particularly, the antibacterialactivity of the present compound against gram-positive strains is farsuperior to that of the known antibacterial agents. In addition, thepresent compound also exhibits a very potent antibacterial activityagainst the strains resistant to the known quinolone compounds.

In view of the pharmacokinetic properties, the compound of the presentinvention has a high water-solubility and thus can be well absorbed inthe living body, in comparison with the known quinolone compounds, toshow a very high bioavailability. The biological half life of thepresent compound is far longer than that of the known quinolonecompounds, and therefore, the present compound can be administered oncea day to be suitably used as an antibacterial agent.

Moreover, since the compound according to the present invention is lesstoxic, it can be effectively used for prophylaxis and treatment ofdiseases caused by bacterial infections in warm-blooded animalsincluding human being.

The present invention will be more specifically explained in thefollowing examples. However, it should be understood that the followingpreparations and examples are intended to illustrate the presentinvention and not to limit the scope of the present invention in anymanner.

PREPARATION 1 Synthesis of (2-cyano-ethylamino)acetic acid ethyl ester##STR22##

139.6 g (1 mole) of glycine ethyl ester hydrochloride was dissolved in80 ml of distilled water and to this solution was added 230 ml of anaqueous solution of 67.3 g (1.2 mole eq.) of potassium hydroxide. Then,106.2 g (2 mole eq.) of acrylonitrile was added to the reaction solutionwhile heating and stirring at 50 to 60° C. The reaction mixture wasstirred for 5 hours with heating and then the organic layer wasseparated. The aqueous layer was extracted with ethyl ether and theextract was combined with the organic layer as separated above. Thecombined organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure to removethe solvent. The residue was distilled under reduced pressure (100 to150° C./10.25 Storr) to obtain 65.6 g (Yield: 48 %) of the titlecompound.

¹ H NMR (CDCl₃ , ppm): δ 4.20(2H, q), 3.48(2H, s), 2.96(2H, t), 2.54(2H,t), 1.30(3H, t); MS (FAB, m/e): 157(M+H)

PREPARATION 2 Synthesis of4-cyano-1-(N-t-butoxycarbonyl)-pyrrolidin-3-one ##STR23##

In the above formula and the following, Boc represents t-butoxycarbonyl.29 g (0.186 mole) of the compound prepared in Preparation 1 wasdissolved in 200 ml of chloroform and the resulting solution wasintroduced into a 1 L flask. Then, 45 g (1.1 mole eq.) ofdi-t-butoxycarbonyldicarbonate was added thereto and the reactionmixture was stirred for 17 hours at room temperature. The reactionsolution was concentrated and the residue was diluted with 250 ml ofabsolute ethanol. The resulting solution was added to sodium ethoxide(NaOEt) solution prepared by adding 6 g of metal sodium (Na) turnings to220 ml of absolute ethanol, under refluxing and heating. The reactionwas continuously conducted for further one hour under refluxing withheating. The reaction solution was concentrated under reduced pressureand the residue was diluted with water and then washed with methylenechloride. The aqueous layer was adjusted with 1N HCl to pH 4 andextracted with ethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then filtered. The filtrate was concentrated toobtain a stoichiometric amount of the title compound in a crude state.

¹ H NMR (CDCl₃ , ppm): δ 4.5-3.5 (5H, m), 1.5(9H, s); MS (FAB, m/e):211(M+H)

PREPARATION 3 Synthesis of4-aminomethyl-1-(N-t-butoxycarponyl)pyrrolidin-3-ol hydrochloride##STR24##

3 g (14 mmole) of the compound prepared in Preparation 2 was dissolvedin the mixture of 357 ml of absolute ethanol and 7 ml of chloroform andthe resulting solution was introduced into a flask. Then, a catalyticamount of platinum oxide(PtO₂) was added thereto. After air was removedfrom the reaction flask under reduced pressure, the reaction mixture wasstirred for 17 hours at room temperature with blowing up the hydrogengas from a balloon filled with hydrogen gas. The reaction solution wasfiltered and the filtrate was concentrated to obtain a stoichicmetricamount of the title compound.

¹ H NMR (CDCl₃, ppm): δ 8.0(2H, bs) 3.5-2.0(7H, m), 3.3(2H, s), 1.38(9H,s); MS (FAB, m/e): 217(M+H)

PREPARATION 4 Synthesis of4-(N-t-butoxycarbonyl)aminomethyl-1-(N-t-butoxycarbonyl)pyrrolidin-3-ol##STR25## Method A:

20 g (0.094 mole) of the compound prepared in Preparation 3 wasdissolved in the mixture of 456 ml of dioxane and 268 ml of distilledwater and the resulting solution was adjusted with 1N aqueous sodiumhydroxide solution to pH 9. Then, 30.9 g (1.5 mole eq.) ofdi-t-butoxycarbonyldicarbonate was added thereto, and the reactionmixture was stirred for 30 minutes at room temperature and concentratedunder reduced pressure. The residue was diluted with nethylene chloride.After adding water to the reaction solution, the organic layer wasseparated and the aqueous layer was acidified to pH 4 and then extractedwith methylene chloride. The extract was combined with the organic layeras separated above and the combined solution was dried over anhydrousmagnesium sulfate and concentrated. The residue was purified with columnchromatography to obtain 17 g (Yield: 57%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 4.95(1H, m), 4.1(1H, m), 3.5(2H, m), 3.3-3.0(4H,m), 2.1(1H, m), 1.45(18H, s); MS (FAB, m/e): 317(M+H)

Method B:

10 g (0.047 mole) of the compound prepared in Preparation 2 wasintroduced into a 1 L flask and then dissolved by adding 500 ml of drytetrahydrofuran. This solution was cooled to -3° C. under ice-sodiumchloride bath and then 3.8 g (0.094 mole) of lithiumaluminumhydride(LAH) was added portionwise thereto over 20 minutes.After the addition is completed, the reaction mixture was stirred forone hour under ice-water bath. When the reaction is completed, 4 ml ofwater, 4 ml of 15% aqueous sodium hydroxide solution and 12 ml of waterwere carefully and successively added to the reaction mixture. The wholemixture was vigorously stirred for 3 hours at room temperature and 10 gof anhydrous magnesium sulfate was added thereto. This mixture wasstirred and then filtered, and the filtrate was concentrated tostoichiometrically obtain the product. The resulting product was dilutedwith 200 ml of dioxane-water (2:1 by volume) and 12.3 g (0.056 mole) ofdi-t-butoxycarbonyldicarbonate was added thereto at room temperature.The reaction solution was stirred for one hour at room temperature tocomplete the reaction and then concentrated. The residue was dilutedagain with ethyl acetate, washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated and the residue was then purified with columnchromatography using hexane-ethyl acetate (2:1 by volume) eluant toobtain 8.2 g (Yield: 55%) of the title compound.

Method C:

210 g (1 mole) of the compound prepared in Preparation 2 was dissolvedin 4 L of methanol and this solution was introduced into a 6 L reactionvessel equipped with a thermometer. The internal temperature of thereaction vessel was cooled to 10° C. under dry ice-acetone bath. 76 g (2mole) of sodium borohydride (NaBH₄) was added portionwise thereto over1.5 hours while maintaining the internal temperature of the vessel at 10to 13° C. After the addition is completed, the reaction mixture wasstirred for further 30 minutes at the same temperature so that all theketone can be reduced to alcohol. Then, 243 g (1 mole) of cobaltchloride hydrate was added thereto over 10 minutes. When the reaction iscompleted, the resulting solid complex was dissolved in 4 L of ammoniawater and this solution was diluted with 8 L of water and then extractedwith ethyl acetate. The organic layer was washed with saturated saline,dried over anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated and mixed with the mixture of 1.5 L of dioxane and 0.5 L ofdistilled water. 212 g of di-t-butoxycarbonyldicarbonate was addedthereto and the whole mixture was stirred for 2 hours at roomtemperature. After the reaction is completed, the reaction mixture wasconcentrated under reduced pressure, diluted again with dichloromethane,washed with water, dried over anhydrous magnesium sulfate and thenfiltered. The filtrate was concentrated and then purified with silicagel column chromatography (eluant:hexane-ethyl acetate 2:1 by volume) toobtain 202 g (Yield: 64%) of the title compound.

Method D:

10 g (0.047 mole) of the compound prepared in Preparation 2 wasintroduced into a 1 L flask and dissolved by adding 500 ml of methanol.This solution was cooled down under ice bath and 3.6 g (0.094 mole) ofsodium borohydride was added portionwise thereto over 20 minutes. Thereaction mixture was stirred for further 30 minutes to complete thereaction, and then concentrated under reduced pressure, diluted withethyl acetate, washed with water, dried over anhydrous magnesium sulfateand then filtered. The filtrate was concentrated to obtain the compoundin which the desired ketone group is reduced to an alcohol. 10.1 g(0.047 mole) of the resulting alcohol compound was dissolved in 200 mlof dry tetrahydrofuran and this solution was cooled down to -5° C. underice-salt bath. 2.6 g (0.066 mole) of lithium aluminumhydride was addedthereto over 20 minutes. The reaction mixture was stirred for further 30minutes at the same temperature to complete the reaction, and then 2.6ml of water, 2.6 ml of 15% sodium hydroxide and 7.8 ml of water wereadded in order thereto. This mixture was stirred for one hour at roomtemperature. After adding 6 g of anhydrous magnesium sulfate, themixture was stirred for further 30 minutes and filtered. The filtratewas concentrated to obtain the product. The resulting product wasdiluted with 200 ml of dioxane-water (2:1 by volume) and 12.3 g (0.056mole) of di-t-butoxycarbonyldicarbonate was added portionwise thereto.The mixture was stirred for 30 minutes to complete the reaction, andthen concentrated, diluted with ethyl acetate, washed with saturatedsaline, dried over anhydrous magnesium sulfate and then filtered. Thefiltrate was concentrated and the residue was purified with columnchromatography to obtain 12.3 g (Yield: 83%) of the title compound.

PREPARATION 5 Synthesis of4-(N-t-butoxycarbonyl)aminomethyl-1-(N-t-butoxycarbonyl)pyrrolidin-3-one##STR26##

14 g (0.044 mole) of the compound prepared in Preparation 4 wasdissolved in 64 ml of dimethylsulfoxide and 18.5 ml (3 mole eq.) oftriethylamine was added thereto. This mixture was cooled down under icebath. When the wall of reaction flask begins to freeze, 12.7 g (1.8 moleeq.) of pyridine-sulfur trioxide(Py--SO₃) oxidant was added portionwisethereto. After the addition is completed, the ice bath was removed andthe reaction solution was stirred for 3 hours at room temperature,diluted with water and then extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and concentrated tostoichicmetrically obtain the title compound in a crude state.

¹ H NMR (CDCl₃, ppm): δ 4.95(1H, bs), 4.15-2.7(6H, m), 2.8(1H, br),1.45(9H, s), 1.40(9H, s); MS (FAB, m/e): 315(M+H)

PREPARATION 6 Synthesis of1-(N-t-butoxycarbonyl)-4-(N-t-butoxycarbonyl)aminomethyl-pyrrolidin-3-oneoxime ##STR27##

300 mg of the compound prepared in Preparation 5 was dissolved in themixture of 6 ml of 95% ethanol and 3 ml of tetrahydrofuran(THF) and thissolution was introduced into a 30 ml reaction vessel. 232 mg (3.5 moleeq.) of hydroxyamine hydrochloride (NH₂ OH.HCl) was added thereto andthen 281 mg (3.5 mole eq.) of sodium hydrogen carbonate dissolved in 1.5ml of distilled water was added. The reaction mixture was stirred for 40minutes at 40° C. under oil bath to complete the reaction, cooled downand then concentrated under reduced pressure. The residue was dilutedwith methylene chloride, washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate and then filtered. Thefiltrate was concentrated and the residue was subjected to silica gelcolumn chromatography eluting with hexane-ethyl acetate (1:1 by volume)to obtain 230 mg (Yield: 73 %) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 9.70(1H, bs), 5.05(1, bs), 4.2(2H, br), 3.83(1H,m), 3.5-3.2(3H,m), 3.0(1H, m), 1.42(18H, s); MS (FAB, m/e): 330(M+H)

PREPARATION 7 Synthesis of1-(N-t-butoxycarbonyl)-4-(N-t-butoxycarbonyl)aminomethyl-pyrrolidin-3-one-benzyloxime##STR28##

659 mg of the compound prepared in Preparation 6, 193 mg oftetra-n-butylammonium bromide and 855 mg of benzyl bromide were added to15 ml of dichloromethane and then 5 ml of 15% aqueous sodium hydroxidesolution was added thereto. The reaction mixture was stirred for 30minutes at room temperature. The organic layer was separated, dried overanhydrous magnesium sulfate and filtered. The filtrate was distilledunder reduced pressure and the residue was purified with glass columnchromatography to obtain 776 mg (Yield: 92%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 7.38(5H, m), 5.13(2H, s), 4.92(1H, m), 4.13(2H,m), 3.76(1H, m), 3.41(1H, m), 3.25(2H, m), 3.02(1H, m), 1.50(9H, s),1.49(9H, s); MS (FAB, m/e): 420(M+H)

PREPARATIONS 8 TO 17

The amine compounds listed in the following Table 1 were preparedaccording to the same procedure as Preparation 7 except that thecorresponding benzylbromide derivatives having R₂ structure as presentedin the following Table 1 are used instead of benzylbromide. ##STR29##

                                      TABLE 1    __________________________________________________________________________    Preparations 8 to 17                                          FAB    Prep.       R.sub.2         NMR(CDCl.sub.3), δ(ppm)                                          MS (M + H)    __________________________________________________________________________    8  4-nitrobenzyl   8.2(2H, m), 7.4(2H, m), 5.2(2H, s), 4.9(1H,                                          465                       s), 4.2(2H, m), 3.8(1H, m), 3.5-3.2(3H, m),                       3.0(1H, m), 1.5(18H, s)    9  4-methoxybenzyl 7.3(2H, m), 6.9(2H, m), 5.0(2H, s), 4.9(1H,                                          450                       s), 4.1(2H, m), 3.8(3H, s), 3.75(1H, m),                       3.5-3.0(4H, m), 1.45(18H, s)    10 4-fluorobenzyl  7.3(2H, m), 7.0(2H, m), 5.0(2H, s), 4.8(1H,                                          438                       br), 4.2(2H, m), 3.9(1H, m), 3.4(3H, m),                       3.0(1H, m), 1.46(18H, s)    11 4-t-butylbenzyl 7.4-7.3(4H, m), 5.1(2H, s), 5.0(1H, s),                                          476                       4.1(2H, m), 3.8(1H, m), 3.6-3.0(4H, m),                       1.45(18H, s), 1.3(9H, s)    12 2-cyanobenzyl   7.8-7.3(4H, m), 5.3(2H, s), 5.0(1H, bs),                                          445                       4.2(2H, s), 3.9(1H, m), 3.6-3.2(3H, m),                       3.0(1H, s), 1.5(18H, s)    13 3-pyridylmethyl 8.6(2H, m), 7.7(1H, m), 7.3(1H, m), 5.1(2H,                                          421                       s), 4.9(1H, s), 4.1(2H, m), 3.8(1H, m),                       3.6-3.2(3H, m), 3.0(1H, m), 1.5(18H, s)    14       1               7.4(2H, m), 6.5(1H, m), 4.9(2H, s), 4.9(1H, s),                       4.1(2H, m), 3.8(2H, m), 3.2(3H, m), 1.5(18H,                                          410    15       2 #STR30##      7.7(2H, m), 7.2(1H, m), 5.5(1H, s), 5.0(1H, s),                       4.2(2H, m), 3.8(1H, m), 3.6-3.1(4H, m), 1.5(18H,                                          495    16       3 #STR31##      6.9(3H, m), 6.0(.2H, m), 5.0(3H, m), 4.1(2H, m),                       3.8(1H, m), 3.6-3.2(3H, m), 3.0(1H, m), 1.5(18H,                                          464    17       4 #STR32##      7.3-7.0(3H, m), 6.8(1H, s), 5.1(1H, s), 4.2(2H, m),                       3.8(1H, m), 3.5-3.0(4H, m), 1.6-1.4(27H,                                          496    __________________________________________________________________________

PREPARATION 18 Synthesis of 4-aminomethyl-pyrrolidin-2-one-benzyloximedihydrochloride ##STR33##

20 ml of methanol was cooled down to 5° C. and then 10 ml of acetylchloride was slowly added thereto. This mixture was stirred for 30minutes and 990 mg of the compound prepared in Preparation 7, which isdissolved in 10 ml of methanol, was added thereto. The reaction mixturewas stirred for 50 minutes at room temperature and concentrated underreduced pressure. The residue was washed with ethyl acetate and dried toobtain 648 mg (Yield: 94%) of the title compound as a yellow solid.

¹ H NMR (DMSO-d₆, ppm): δ 10.0(1H, m), 8.35(2H, m), 7.40(5H, m),5.18(2H, s), 4.00(2H, m), 3.69(1H, m), 3.40(2H, m), 3.12(2H, s); MS(FAB, m/e): 220(M+H)

PREPARATIONS 19 TO 28

The compounds listed in the following Table 2 were prepared from theamine compounds prepared in Preparations 8 to 17 according to the sameprocedure as Preparation 18. ##STR34##

                                      TABLE 2    __________________________________________________________________________    Preparations 19 to 28                                          FAB    Prep.       R.sub.2         NMR(CDCl.sub.3), δ(ppm)                                          MS (M + H)    __________________________________________________________________________    19 4-nitrobenzyl   10.3-10.1(2H, s), 8.3(3H, d),                                          265                       7.7(2H, d), 5.3(2H, s), 4.1(2H, m), 3.7(1H,                       m), 3.4(2H, m), 3.1(2H, m)    20 4-methoxybenzyl 10.2-10.0(2H, s), 8.4(3H, s), 7.3(2H,                                          250                       6.9(2H, d), 5.0(2H, s), 3.9(2H, m), 3.73(3H,                       s), 3.7(1H, m), 3.4(2H, m), 3.1(2H, m)    21 4-fluorobenzyl  10.2(2H, s), 8.4(3H, s), 7.3(2H, m),                                          238(2H,                       m), 5.1(2H, s), 3.9(2H, m), 3.7(1H, m),                       3.4(2H, m), 3.1(2H, m)    22 4-t-butylbenzyl 10.2(2H, s), 8.4(3H, s), 7.4-7.3(4H,                                          276                       5.1(2H, s), 3.9(2H, m), 3.7(1H, m), 3.2                       (2H, m), 3.1(2H, m), 1.3(9H, s)    23 2-cyanobenzyl   10.2-10.0(2H,s), 8.2(3H, s), 7.9-7.5(4H,                                          245                       m), 5.3(2H, s), 4.0(2H, m), 3.7(1H, m),                       3.2(2H, m), 3.1(2H, m)    24 3-pyridylmethyl 10.3(1H, s), 10.1(1H, s), 8.9(1H, s),                                          221                       (1H, m), 8.5(1H, d), 8.4(3H, m), 8.0(1H, m),                       5.4(2H, s), 4.0(2H, m), 3.7(1H, m), 3.4                       (2H, m), 3.1(2H, m)    25       1               10.3(2H, s), 8.4(3H, s), 7.6(1H, s), 6.4(1H, s),                       5.0(2H, s), 4.0(2H, m), 3.8(1H, m), 3.4(2H, m),                       3.1(2H, m)         210    26       2 #STR35##      10.3(2H, s), 8.3(3H, s), 8.1(1H, m), 7.9 (1H, m),                       7.4(1H, m), 5.5(2H, s), 4.1(2H, m), 3.9(1H, m),                       3.14(2H, m), 3.1(2H, m)                                          295    27       3 #STR36##      10.2(2H, s), 8.3(3H, s), 7.0(3H, m), 6.3 (2H, s),                       5.3(2H, m), 4.1(2H, m), 3.9(1H, m), 3.4-3.2(2H, m),                       3.1(2H, m)         264    28       4 #STR37##      10.3-10.2(2H, s), 8.4(3H, s), 8.0-7.3(3H, m), 7.0(1H,                       s), 4.2(2H, m), 3.8(1H, m), 3.5-3.2(3H, m), 3.0(1H,                                          296    __________________________________________________________________________

PREPARATION 29 Synthesis of1-(N-t-butoxycarbonyl)-4-t-butoxycarbonyl)-aminomethyl-pyrrolidin-3-onet-butyloxime ##STR38##

300 mg of the compound prepared in Preparation 5 was dissolved in themixture of 6 ml of 95% ethanol and 3 ml of tetrahydrofuran(THF) and thissolution was introduced into a 30 ml reaction vessel. 487 mg (3.5 moleeq.) of o-t-butylhydroxyamine hydrochloride was added thereto and then281 mg (3.5 mole eq.) of sodium hydrogen carbonate dissolved in 1.5 mlof distilled water was added. The reaction mixture was stirred for 40minutes at 40° C. under oil bath to complete the reaction, and thencooled down, concentrated under reduced pressure, diluted with methylenechloride, washed with saturated aqueous sodium chloride solution, driedover anhydrous magnesium sulfate and then filtered. The filtrate wasconcentrated and the residue was subjected to silica gel columnchromatography eluting with hexane-ethyl acetate (1:1 by volume) toobtain 285 mg (Yield: 80%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 5.10(1H, bs), 4.05(2H, s), 3.71(1H, dd),3.43(1H, br), 3.2(2H, m), 3.0(1H, m), 1.42(13H, s), 1.30(9H, s); MS(FAB, m/e): 386(M+H)

PREPARATION 30 Synthesis of1-(N-t-butoxycarbonyl)-4-(N-t-butoxycarbonyl)aminomethyl-pyrrolidin-3-one3-butynyloxime ##STR39## A. Synthesis of 3-butynyl hydroxylamine

0.35 g (5 mmole) of 3-butynol, 0.86 g (5.25 mmole) ofN-hydroxyphthalinide and 1.44 g (5.5 mmole) of triphenylphosphine weredissolved in 15 ml of dry tetrahydrofuran, and then 1.05 g (6 mmole) ofdiethylazodicarboxylate was added thereto over 30 minutes. The mixturewas stirred for 10 minutes at room temperature and then distilled underreduced pressure to remove the solvent. To the residue was added 50 mlof ethyl acetate-hexane (1:1 v/v). The precipitated solid material wasfiltered off and the filtrate was concentrated. The residue was purifiedwith column chromatography (hexane-ethyl acetate 9:1 v/v). The resultingwhite solid 0.54 g, Yield 50%, ¹ H NMR (CDCl₃, ppm): δ 7.85(2H, m),7.75(2H, m), 4.2(2H, t), 2.8(2H, dd), 2.5(2H, dd), 2.1(1H, s), FABMS(POS): M+H!⁺ =216! was dissolved in 12 ml of methylene chloride, and0.25 g (5 mmole) of hydrazine hydrate diluted with 4 ml of methanol wasadded dropwise thereto. The solid precipitate was filtered off and thefiltrate was concentrated at low temperature under reduced pressure toobtain 0.2 g (Yield: 93%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 9.5(2H, br), 4,5(2H, t), 2.8(2H, m), 2.4(2H, m),2.05(1H, s); MS (FAB, m/e): 86(M+H)⁺

B. Synthesis of the title compound

0.45 g (1.43 mmole) of the compound prepared in Preparation 5 and 0.2 g(2.35 mmole) of 3-butynyl hydroxyamine were dissolved in 5 ml ofmethanol and the reaction was conducted for 12 hours at 60° C. Thereaction solution was concentrated under reduced pressure and theresidue was subjected to column chromatography (ethyl acetate-hexane 1:4v/v) to obtain 0.59 g (stoichiometric amount) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 5.0(1H, m), 4.15(2H, t), 4.0(2H, s), 3.75(1H,m), 3.6-3.2(3H, m), 3.0(1H, m), 2.5(2H, m), 2.0(1H, s), 1.45(18H, s);FAB MS (POS): 332(M+H)⁺

PREPARATIONS 31 TO 36

The amine compounds listed in the following Table 3 were preparedaccording to the same procedure as Preparation 30 exceptthat thecorresponding alcohol derivatives having R₂ structure as represented inthe following Table 3 are used instead of 3-butynol. ##STR40##

                                      TABLE 3    __________________________________________________________________________    Preparations 31 to 36                                    FAB    Prep.       R.sub.2  .sup.1 H NMR(CDCl.sub.3), δ(ppm)                                    MS (M + H)    __________________________________________________________________________    31 isopropyl                5.0(1H, br), 4.1(2H, s), 4.0(1H, m), 3.4                                    372                (1H, m), 3.55-3.25(3H, m), 3.0(1H, m),                1.55(18H, s), 1.0(6H, d)    32 cyclobutyl                4.7(1H, m), 4.2(2H, s), 3.8(1H, m), 3.4(1H,                                    384                m), 3.3(2H, m), 3.0(1H, m), 2.3(2H, m), 2.1                (2H, m), 1.8(1H, m), 1.6(1H, m), 1.5(18H, s)    33 cyclopentyl                4.7(1H, m), 4.1(2H, m), 3.7(1H, m),                                    398                3.4(1H, m), 3.3(2H, m), 3.0(1H, m),                1.8(4H, m), 1.7(4H, m), 1.6(18H, s)    34       5        5.0-4.8(1H, m), 4.3-3.7(6H, m), 3.3(2H, m), 3.0(1H, m),                2.1(2H, m), 1.5(18H, s), 1.3(2H, m)                                    400    35 cyclopropyl-                5.1(1H, br), 4.1(2H, m), 3.9(2H, m), 3.8(1H,                                    384       methyl   m), 3.5(1H, m), 3.3(2H, m), 3.0(1H, m), 1.5                (18H, s), 1.1(1H, m), 0.6(2H, s), 0.3(2H, s)    36 isobutyl 5.05(1H, br), 4.15(2H, s), 4.1(2H, d),                                    386                3.6(2H, m), 3.3(1H, m), 3.0(2H, m),                2.5(1H, m), 1.5(18H, s), 1.05(6H, d)    __________________________________________________________________________

PREPARATION 37 Synthesis of1-(N-t-butoxycarbonyl)-4-(N-t-butoxycarbonyl)aminomethyl-pyrrolidin-3-onepropargyl oxime ##STR41##

659 mg of the compound prepared in Preparation 6, 193 mg oftetra-n-butylammonium bromide and 855 mg of propargyl bromide were addedto 15 ml of dichloromethane, and 5 ml of 15% aqueous sodium hydroxidesolution was added thereto. This mixture was stirred for 30 minutes atroom temperature. The organic layer was separated, dried over anhydrousmagnesium sulfate and then filtered. The filtrate was distilled underreduced pressure and the residue was purified with glass columnchromatography to obtain 776 mg (Yield: 92%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 4.92(1H, m), 4.13(2H, m), 3.76(1H, 3.41(1H, m),3.25(2H, m), 3.02(1H, m), 1.50(9H, s), 1.49(9H, s); MS (FAB, m/e):368(M+H)

PREPARATIONS 38 AND 39

The amine compounds listed in the following Table 4 were preparedaccording to the same procedure as Preparation 37 except that thecorresponding alkyl derivatives having R₂ structure as represented inthe following Table 4 are used instead of propargyl. ##STR42##

                  TABLE 4    ______________________________________    Preparations 38 and 39                                       FAB    Prep.         R.sub.2  .sup.1 H NMR(CDCl.sub.3), δ(ppm)                                       MS(M + H)    ______________________________________    38   methoxy- 5.15-4.9(3H), 4.15(2H, m),                                       374         methyl   3.75(1H, m), 3.5-3.2(5H), 3.0(1H, m),                  1.5(18H, s)    39   2-chloro-                  4.9(1H, m), 4.3(2H, t), 4.1(2H, s),                                       392         ethyl    3.7(3H, m), 3.6(1H, m), 3.5-                  3.0(3H, m), 1.45(18H, s)    ______________________________________

PREPARATION 40 Synthesis of 4-aminomethyl-pyrrolidin-3-one t-butyloximedihydrochloride ##STR43##

5 ml of methanol was cooled down to 0° C. and 3 ml of acetyl chloridewas slowly added thereto. This mixture was stirred for 10 minutes and640 mg of the compound prepared in Preparation 29, which is dissolved in10 ml of methanol, was added thereto. The reaction mixture was stirredfor 20 minutes at room temperature and concentrated under reducedpressure. The residue was filtered, washed with ethylether and dried toobtain 390 mg (Yield: 91%) of the title compound as a white solid.

¹ H NMR (DMSO-d₆, ppm): δ 10.0-9.6(2H, bsX2), 8.20(3H, br), 3.90(2H,dd),3.61(1H, bs), 3.40(2H, bs), 3.12(2H, bs), 1.25(9H, s); MS (FAB, m/e):186(M+H)

PREPARATIONS 41 TO 50

The compounds of Preparations 41 to 50 as listed in the following Table5 were prepared from the compounds prepared in Preparations 30 to 40according to the same procedure as Preparation 40. ##STR44##

                                      TABLE 5    __________________________________________________________________________    Preparations 41 to 50                                    FAB    Prep.       R.sub.2  .sup.1 H NMR(CDCl.sub.3), δ(ppm)                                    MS (M + H)    __________________________________________________________________________    41 CH.sub.2 CH.sub.2 C.tbd.CH                10.1-9.8(2H, br), 8.2(3H, br), 4.3(2H, t),                                    182                4.0(2H, s), 3.7(1H, m), 3.6-3.2(3H, m),                3.0(1H, m), 2.8(1H, s), 2.6(2H, t)    42 isopropyl                10.1-9.8(2H,br), 8.3(3H, br), 4.4(1H, m),                                    172                3.9(2H, d), 3.7(1H, m), 3.3(2H, s),                3.1(2H, m), 1.2(6H, d)    43 cyclobutyl                10.2-9.8(2H, br), 8.2(3H, br), 4.8(1H, m),                                    184                4.3(2H, s), 3.7(1H, m), 3.6-3.2(3H, m),                3.0(1H, m), 1.8(2H, m), 1.7(2H, m),                1.5(1H, m), 1.45(1H, m)    44 cyclopentyl                10.2-9.8(2H, br), 8.2(3H, br), 4.7(1H, m),                                    198                4.3(2H, s), 3.8(1H, m), 3.3(1H, m), 3.2(3H,                m), 1.8(4H, m), 1.6(2H, m), 1.5(2H, m)    45       5        10.1-9.8(2H, br), 8.3(3H, s), 4.1-3.6 (10H, m), 3.2(2H, s),                2.2-1.9(2H, m)      200    46 cyclopropyl-                10.1-9.8(2H, br), 8.3(3H, s), 4.0-3.8                                    184       methyl   (4H, m), 3.65(1H, m), 3.4(2H, m), 3.1(2H, m),                1.1(1H, m), 0.5(2H, d), 0.2(2H, d)    47 isobutyl 10.3-9.9(2H, br), 8.4(3H, br), 3.9-3.8                                    186                (4H, m), 3.65(1H, m), 3.3(2H, s), 3.1(2H, m),                1.9(1H, m), 0.85(6H, d)    48 propargyl                10.0(1H, m), 8.3(2H, m), 4.8(2H, s),                                    168                4.0(2H, m), 3.7(1H, m), 3.6(1H, s)                3.4(2H, m), 3.1(2H, s)    49 methoxymethyl                10-9.6(2H, br), 8.2(3H, br), 5.1(2H, dd)                                    174                4.1-3.8(2H, m), 3.7(1H, m), 3.3-3.0(4H, m)    50 2-chloroethyl                10-9.7(2H, br), 8.2(3H, br), 4.3(2H, t),                                    192                4.0(2H, m), 3.8(2H, t), 3.7(1H, m),                3.4(2H, m), 3.2(1H, m), 3.1(2H, m)    __________________________________________________________________________

PREPARATION 51 Synthesis of4-(N-t-butoxycarbonyl)aminomethyl-1-(N-t-butoxycarbonyl)pyrrolidin-3-oneo-methyloxime ##STR45##

260 mg (3.28×10⁻⁴ mole) of the compound prepared in Preparation 5 wasdissolved in the mixture of 65 ml of 95% ethanol and 2.5 ml oftetrahydrofuran and this solution was introduced into a reaction vessel.Then, 256 mg (3.7 mole eq.) of methoxyamine hydrochloride was addedthereto and 257 mg (3.7 mole eq.) of sodium hydrogen carbonate(NaHCO₃)dissolved in 2.5 ml of distilled water was also added. The reactionmixture was stirred for 1 hours at 40° C. under oil bath, concentratedunder reduced pressure, washed successively with aqueous ammoniumchloride solution and aqueous sodium chloride solution, dried overanhydrous magnesium sulfate and then filtered. The filtrate wasconcentrated to obtain 250 mg (Yield: 88%) of the title compound.

¹ H NMR (CDCl₃, ppm): δ 4.98(1H, bs), 3.81(3H, s), 3.75-2.80(7H, m),1.40(1H, s); MS (FAB, m/e): 344(M+H)

PREPARATIONS 52 AND 53

The compounds listed in the following Table 6 were prepared according tothe same procedure as Preparation 51 except that phenoxyaminehydrochloride or ethoxyamine hydrochloride are used instead ofmethoxyanine hydrochloride. ##STR46##

                  TABLE 6    ______________________________________    Preparations 52 and 53                                       FAB    Prep. R.sub.2    .sup.1 H NMR(CDCl.sub.3), δ(ppm)                                       MS(M + H)    ______________________________________    52    phenyl     7.3(5H, m), 4.97(1H, bs), 3.8-                                       406                     2.8(7H, m), 1.40(18H, s)    53    --CH.sub.2 CH.sub.3                     5.0(1H, bs), 3.8-2.8(7H, m),                                       358                     1.42(18H, s), 1.41(18H, s),                     1.38(3H, t)    ______________________________________

PREPARATION 54 Synthesis of 4-aminomethyl-pyrrolidin-3-one O-methyloximeditrifluoroacetate ##STR47##

5 ml of trifluoroacetic acid was added to 250 mg of the compoundprepared in Preparation 51, and this mixture was stirred for 20 minutesat room temperature. The reaction mixture was concentrated under reducedpressure, dissolved in the smallest amount of acetonitrile and thensolidified with ethylether to obtain 220 mg (Yield: 84%) of the titlecompound in a purified state.

¹ H NMR (CD₃ OD, ppm): δ 4.1(2H, s), 3.96(3H, s), 3.83(1H, dd),3.7-3.2(6H, m); MS (FAB, m/e): 144(M+H)

PREPARATIONS 55 TO 57

The corresponding compounds of Preparations 55 to 57 were prepared fromthe compounds prepared in Preparations 6, 52 and 53, respectively,according to the same procedure as Preparation 54. ##STR48##

                  TABLE 7    ______________________________________    Preparations 55 to 57                                       FAB    Prep. R.sub.2    .sup.1 H NMR(CDCl.sub.3), δ(ppm)                                       MS(M + H)    ______________________________________    55    --H        4.1-3.2(7H, m)    130    56    --Ph       7.2-7.4(5H, m), 4.1-3.2(7H, m)                                       206    57    --CH.sub.2 CH.sub.3                     4.2-3.1(9H, m), 1.3(3H, t)                                       158    ______________________________________

EXAMPLE 1 Synthesis of7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid ##STR49##

622 mg of7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid and 643 mg of the compound prepared in Preparation 18 weresuspended in 15 ml of acetonitrile. This suspension was cooled downunder ice-water bath and then 1.0 ml of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for 1.5 hours at room temperature and, after adding 15 ml ofwater, was then concentrated. The concentrated suspension was filtered.The filtered solid product was washed with water and ethanol to obtain534 mg (Yield: 57%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.59(1H, s), 8.03(1H, d), 7.40(5H, m),5.14(2H, s), 4.75(2H, s), 4.18(1H, m), 3.94(1H, m), 3.83(1H, m),3.35(2H, m), 3.05(1H, m), 2.81(1H, m), 2.73(1H, m), 1.25-1.05(4H, m); MS(FAB, m/e): 466(M+H)

EXAMPLES 2 TO 11

The same starting material as Example 1 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the saneprocedure as Example 1 to prepare the respective compounds listed in thefollowing Table 8.

                                      TABLE 8    __________________________________________________________________________    Examples 2 to 11    6 #STR50##                                         FAB, Reac.    Examp.                          NMR  MS   time                                                 Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                         (M + 1)                                              (min)                                                 (%)    __________________________________________________________________________        7 #STR51##   8.73(1H, s), 8.05(1H, d), 7.30 (2H, d), 6.98(2H, d),                     5.10(2H, s), 4.61(2H, s), 4.25(1H, m), 3.90(1H, m),                     3.80(3H, s), 3.70 (1H, m), 3.00(3H, m), 1.26(2H, m),                     1.07(2H, m)    CDCl.sub.3                                         496  10 75    3        8 #STR52##   8.75(1H, s), 8.05(1H, d), 7.45 (2H, d), 7.30(2H, d),                     5.15(2H, s), 4.62(2H, s), 4.25(1H, m), 3.85(1H, m),                     3.75(1H, m), 3.10 (1H, m), 2.98(2H, m), 1.35(9H, s),                     1.25(2H, m), 1.09(2H, m)                                    CDCl.sub.3                                         522  15 76    4        9 #STR53##   8.68(1H, s), 8.00(1H, d), 7.35 (2H, m), 7.10(2H, m),                     5.08(2H, s), 4.59(2H, s), 4.20(1H, m), 3.95(1H, m),                     3.81(1H, m), 3.00 (3H, m), 1.23(2H, m), 1.04(2H,                                    CDCl.sub.3                                         484  15-                                                 80    5        0 #STR54##   8.59(1H, s), 8.21(2H, d), 8.06 (1H, s), 7.64(2H, d),                     5.29(2H, s), 4.68(2H, s), 4.20(1H, m), 3.95(1H, m),                     3.85(1H, m), 3.10 (1H, m), 2.80(2H, m), 1.18(2H, m),                     1.10(2H, m)    DMSO 511  10 76    6        1 #STR55##   8.58(1H, s), 8.05(1H, d), 7.92 -7.42(4H, m), 5, 28(2H,                     s), 4.65(2H, s), 4.20(1H, m),3.95 (1H, m), 3.78(1H, m),                     3.10(1H, m), 2.80(2H, m), 1.20(2H, m), 1.09(2H,                                    DMSO 491  20 82    7        2 #STR56##   8.74(1H, s), 8.10(1H, d), 6.92 (3H, m), 6.10(2H,s),                     5.10(2H, s), 4.75(2H, s), 4.30(1H, m), 3.95(1H, m),                     3.85(1H, m), 3.15 (1H, m), 3.10(2H, m), 1.28(2H, m),                     1.09(2H, m)    CDCl.sub.3                                         510  25 79    8        3 #STR57##   8.60(1H, d), 8.57(1H, s), 8.52 (1H, d), 8.03(1H, d),                     7.80(1H, d), 7.41(1H, q), 5.18(2H, s), 4.65(2H, s),                     4.17(1H, m), 3.94 (1H, m), 3.75(1H, m), 3.30(2H, m),                     3.04(1H, m), 2.81(1H, m), 2.73(1H, m), 1.30-1.00(4H,                                    DMSO-d.sub.6                                         467  90 70    9        4 #STR58##   8.82(1H, s), 8.05(1H, d), 7.51 (1H, d), 7.45(1H, m),                     6.5(1H, s), 5.02(2H, m), 4.5(2H, m), 4.20(1H, m),                     3.95(1H, m), 3.70 (1H, m), 3.00(1H, m), 2.80(1H, m),                     2.70(1H, m), 1.00(4H, m)                                    DMSO 456  15 69    10        5 #STR59##   8.58(1H, s), 8.00(1H, d), 7.10 (3H, m), 6.72(1H, s),                     4.80(2H, s), 4.20(1H, m), 3.95(1H, m), 3.85(1H, m),                     3.10(1H, m), 2.95 (2H, m), 1.07(4H, m)                                    DMSO 542  20 65    11        6 #STR60##   8.76(1H, s), 8.20(1H, m), 8.02 (1H, d), 7.89(1H, m),                     7.40(1H, m), 5.60(2H, s), 4.78(2H, m), 4.45(1H, m),                     3.85(1H, m), 3.70 (1H, m), 3.10(2H, m), 1.30(2H, m),                     1.15(2H, m)    DMSO 541  25 73    __________________________________________________________________________

EXAMPLE 12 Synthesis of7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR61##

530 mg of1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acidand 584 mg of the compound prepared in Preparation 8 were suspended in15 ml of acetonitrile. This suspension was cooled down under ice-waterbath and then 913 mg of 1,8-diazabicyclo 5.4.0!undec-7-ene(DBU) wasslowly added thereto. The reaction mixture was stirred for 2 hours at80° C. and, after adding 15 ml of water, was then concentrated. Theconcentrated suspension was filtered. The filtered solid product waswashed with water and ethanol to obtain 631 mg (Yield: 68%) of the titlecompound.

¹ H NMR (DMSO-d₆, ppm): δ 8.60(1H, s), 7.92(1H, d), 7.38(5H, m),5.10(2H, s), 4.87(2H, s), 4.10(1H, m), 3.94(1H, m), 3.86(1H, m),3.37(2H, m), 3.02(1H, m), 2.38(1H, m), 2.73(1H, m), 1.25-1.05(4H, m); MS(FAB, m/e): 465(M+H)

EXAMPLES 13 TO 22

The same starting material as Example 12 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 12 to prepare the respective compounds listed inthe following Table 9.

                                      TABLE 9    __________________________________________________________________________    Examples 13 to 22    7 #STR62##                                         FAB, Reac.    Examp.                          NMR  MS   time                                                 Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                         (M + 1)                                              (min)                                                 (%)    __________________________________________________________________________    13        7 #STR63##   8.6(1H, s), 7.8(1H, d), 7.2(3H, d), 6.9(2H, d), 5.1(2H,                     s), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(3H, s),                     3.65(1H, m), 3.0 (1H, m), 2.9-2.7(2H, m), 1.3- 7 1.1(4H,                     m)             DMSO-d.sub.6                                         495  2  60    14        8 #STR64##   8.6(1H, s), 7.8(1H, d), 7.4(2H, d), 7.3(3H, m), 5.1(2H,                     sd), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m),                     3.0(1H, m), 2.9-2.7 (2H, m), 1.4(9H, s), 1.3-1.1 (4H,                                    DMSO-d.sub.6                                         521  2  65    15        9 #STR65##   8.6(1H, s), 7.8(1H, d), 7.4(2H, m), 7.2(3H, m), 5.1(2H,                     s), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m),                     3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H,                                    DMSO-d.sub.6                                         483  4  67    16        0 #STR66##   8.6(1H, s), 8.2(2H, d), 7.8(1H, d), 7.6(2H, d), 7.2(1H,                     d), 5.3 (2H, s), 4.4(1H, s), 3.9(1H, m), 3.8(1H, m),                     3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H,                                    DMSO-d.sub.6                                         510  3  58    17        1 #STR67##   8.6(1H, s), 7.9-7.4(5E, m), 7.2 (1H, d), 5.3(2H, s),                     4.4(2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H,                     m), 2.9-2.7 (2H, m), 1.3-1.1(4H, m)                                    DMSO-d.sub.6                                         490  4  55    18        2 #STR68##   8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 6.9(3H, m), 6.1(2H,                     s), 5.1 (2H, s), 4.4(2H, s), 3.9(1H, m), 3.8(1H, m),                     3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H,                                    DMSO-d.sub.6                                         509  4  71    19        3 #STR69##   8.6(3H, m), 7.8(2H, m), 7.4(1H, q), 7.2(1H, d), 5.2(2H,                     s), 4.4 (1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m),                     3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H,                                    DMSO-d.sub.6                                         466  4  53    20        4 #STR70##   8.6(1H, s), 7.8(1H, d), 7.5(2H, m), 7.2(1H, d), 6.5(1H,                     m), 5.0 (2H, m), 4.4(1H, m), 3.9(1H, m), 3.8(1H, m),                     3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H,                                    DMSO-d.sub.6                                         455  4  60    21        5 #STR71##   8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 7.1(3H, m), 6.7(1H,                     s), 4.4 (1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m),                     3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H,                                    DMSO-d.sub.6                                         541  4  50    22        6 #STR72##   8.6(1H, s), 8.2(1H, m), 7.9-7.8 (2H, m), 7.4(1H, m),                     7.2(1H, d), 5.6(2H, s), 4.4(1H, m), 3.9(1H, m), 3.8(1H,                     m), 3.0(1H, m), 2.9- 2.7(2H, m), 1.3-1.1(4H,                                    DMSO-d.sub.6                                         540  4  70    __________________________________________________________________________

EXAMPLE 23 Synthesis of7-(4-aminomethyl-3-benzyloximino-pyrrolidin-1-yl-1-cyclopyropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid ##STR73##

566 mg of1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid and 584 mg of the compound prepared in Preparation 8 were suspendedin 15 ml of acetonitrile. This suspension was cooled down underice-water bath and then 913 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for 2 hours at 80° C. and, after adding 10 ml of water, wasthen concentrated. The concentrated suspension was filtered. Thefiltered solid product was washed with water and ethanol to obtain 704mg (Yield: 73%) of the title. compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.64(1H, s), 7.99(1H, d), 7.41(5H, m),5.10(2H, s), 4.73(2H, s), 4.18(1H, m) 3.92(1H, m), 3.86(1H, m), 3.37(2H,m), 3.02(1H, m), 2.83(1H, m), 2.73(1H, m), 1.25-1.05(4H, m); MS (FAB,m/e): 483(M+H)

EXAMPLES 24 TO 33

The same starting material as Example 23 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 23 to prepare the respective compounds listed inthe following Table 10.

                                      TABLE 10    __________________________________________________________________________    Examples 24 to 33    1 #STR74##                                        FAB.,                                            Reac.    Examp.                          NMR MS  time                                               Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                        (M + 1)                                            (hr)                                               (%)    __________________________________________________________________________    24        2 #STR75##   8.6(1H, s), 7.7(1H, d), 7.2(2H,d), 6.9(2H, d), 5.1(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     3.7(3H, s), 2.9(H,m), 2.8-2.7(2H, m), 1.15(4H,                                    DMSO-d.sub.6                                        513 2  75    25        3 #STR76##   8,6(1H, s), 7.7(1H, d), 7.5(2H,m), 7.1(2H, m), 5.1(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.7(2H, m), 1.4(9H, s), 1.15(4H,                                    DMSO-d.sub.6                                        539 4  70    26        4 #STR77##   8.6(1H, s), 7.7(1H, d), 7.3(2H,m), 7.1(2H, m), 5.1(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m)                                    DMSO-d.sub.6                                        501 4  80    27        5 #STR78##   8.6(1H, s), 8.2(2H, d), 7.7(1H,d), 7.6(2H, d), 5.3(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m)                                    DMSO-d.sub.6                                        528 3  68    28        6 #STR79##   8.6(1H, s), 7.9-7.4(5H, m), 5.3(2H, s), 4.3(2H, s),                     4.1(1H, m),3.9(1H, m), 3.8(1H, m), 2.9(1H,m),                     2.8-2.7(2H, m), 1.15(4H, m)                                    DMSO-d.sub.6                                        508 2  70    29        7 #STR80##   8.6(1H, s), 7.1(1H, d), 7.0(3H,m), 6.1(2H, s), 5.1(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m)                                    DMSOd.sub.6                                        527 3  69    30        8 #STR81##   8.6(3H, m), 7.8(1H, d), 7.7(1H,d), 7.4(1H, q), 5.3(2H,                     s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m)                                    DMSO-d.sub.6                                        484 3  58    31        9 #STR82##   8.6(1H, s), 7.7(1H, d), 7.5(2H,m), 6.5(1H, m), 5.0(2H,                     m), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m),3.8(1H, m),                     2.9(1H, m), 2.8-2.,7(2H, m), 1.15(4H, m)                                    DMSO-d.sub.6                                        473 3  70    32        0 #STR83##   8.6(1H, s), 7.7(1H, d), 7.1(3H,m), 6.6(1H, s), 4.3(2H,                     s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m),2,9(1H, m),                     2.8-2.7(2H, m),1.15(4H, m)                                    DMSO-d.sub.6                                        559 4  59    33        1 #STR84##   8.6(1H, s), 8.3(1H, m), 7.9(1H,m), 7.7(1H, d), 7.4(1H,                     m), 5.6(2H, s), 4.3(2H, s), 4.1(1H, m),3.9(1H, m),                     3.8(1H, m), 2.9(1H,m), 2.8-2.7(2H, m), 1.15(4H,                                    DMSO-d.sub.6                                        558 4  60    __________________________________________________________________________

EXAMPLE 34 Synthesis of7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylicacid ##STR85##

598 mg of8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 584 mg of the compound prepared in Preparation 8 were suspendedin 15 ml of acetonitrile and then 913 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for 3 hours at 80° C. and, after adding 15 ml of water, wasthen concentrated. The concentrated suspension was filtered. Thefiltered solid product was washed with water and ethyl ether to obtain510 mg (Yield: 52%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.78(1H, s), 7.91(1H, d), 7.41(5H, m),5.16(2H, s), 4.74(2H, s), 4.16(1H, m), 3.90(1H, m), 3.85(1H, m),3.35(2H, m), 3.02(1H, m), 2.82(1H, m), 2.75(1H, m), 1.30-1.10(4H, m); MS(FAB, m/e): 499(M+H)

EXAMPLES 35 to 44

The same starting material as Example 34 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 34 to prepare the respective compounds listed inthe following Table 11.

                                      TABLE 11    __________________________________________________________________________    Examples 35 to 44    2 #STR86##                                        FAB,                                            Reac.    Examp.                          NMR MS  time                                               Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                        (M + 1)                                            (hr)                                               (%)    __________________________________________________________________________    35        2 #STR87##   8.7(1H, s), 7.9(1H, d), 7.3(2H,d), 7.0(2H, d), 5.1(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.7(3H, s),                     3.0(1H, m), 2.9-2.6(2H, s), 1.2-0.9(4H,                                    DMSO-d.sub.6                                        529 3  43    36        3 #STR88##   8.7(1H, s), 7.9(1H, d), 7.5(2H,d), 7.3(2H, d), 5.2(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H, m),                     2.9-2.7(2H, m), 1.4(9H, s), 1.2-0.9(4H,                                    DMSO-d.sub.6                                        555 3  73    37        4 #STR89##   8.7(1H, s), 7.9(1H, d), 7.4(2H,m), 7.1(2H, m), 5.1(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H, m),                     2.9-2.7(2H, m),1.2-0.9(4H, m)                                    DMSO-d.sub.6                                        517 2  80    38        5 #STR90##   8.7(1H, s), 8.3(2H, d), 7.9(1H,d), 7.7(2H, d), 5.4(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H, m),                     2.9-2.7(2H, m),1.2-0.9(4H, m)                                    DMSO-d.sub.6                                        544 4  63    39        6 #STR91##   8.7(1H, s), 7.9-7.4(5H, m), 5.3(2H, s), 4.4(2H, s),                     4.3(1H, m),3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m),                     1.2-0.9(4H, m) DMSO-d.sub.6                                        524 4  70    40        7 #STR92##   8.7(1H, s), 7.9(1H, d), 7.0(3H,m), 6.1(2H, s), 5.1(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H, m),                     2.9-2.7(2H, m),1.2-0.9(4H, m)                                    DMSO-d.sub.6                                        543 2  67    41        8 #STR93##   8.7(1H, s), 7.9(1H, d), 8.6(2H,m), 7.8(1H, d), 7.4(1H,                     q), 5.2(2H, s), 4.4(2H, s), 4.3(1H, m),3.8(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H,                                    DMSO-d.sub.6                                        500 4  60    42        9 #STR94##   8.7(1H, s), 7.9(1H, d), 7.5(2H,m), 6.5(1H, m) , 5.0(2H,                     m), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H,                     m)12.9-2.7(2H, m),1.2-0.9 (4H, m)                                    DMSO-d.sub.6                                        489 2  62    43        6 #STR95##   8.7(1H, s), 7.9(1H, d), 7.1(3H,m), 6.7(1H, s), 4.4(2H,                     s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m),2.9-2.6(2H, m),                     1.2-0.9(4H, m) DMSO-d.sub.6                                        575 4  60    44        1 #STR96##   8.7(1H, s), 8.2(1H, m), 7.9(2H,m), 7.4(1H, m), 5.6(2H,                     s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m),3.0(1H, m),                     2.9-2.7(2H, m),1.2-0.9(4H, m)                                    DMSO-d.sub.6                                        574 4  76    __________________________________________________________________________

EXAMPLE 45 Synthesis of7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR97##

590 mg of1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 584 mg of the compound prepared in Preparation 8 were suspendedin 15 ml of acetonitrile and then 913 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for 2 hours at 80° C. and, after adding 15 ml of water, wasthen stirred for 30 minutes at room temperature and filtered. Thefiltered solid product was washed with water and ethyl ether to obtain465 mg (Yield: 47%) of the title compound.

¹ H NHR (DMSO-d₆, ppm): δ 8.61(1H, s), 7.99(1H, d), 7.40(5H, m),5.15(2H, s), 4.74(2H, s), 4.17(1H, m), 3.95(1H, m), 3.83(1H, m),3.60(3H, s), 3.35(2H, m), 3.02(1H, m), 2.80(1H, m), 2.71(1H, m),1.30-1.10(4H, m); MS (FAB, m/e): 495(M+H)

EXAMPLES 46 to 55

The same starting material as Example 45 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 45 to prepare the respective compounds listed inthe following Table 12.

                                      TABLE 12    __________________________________________________________________________    Examples 46 to 55    3 #STR98##                                        FAB,                                            Reac.    Examp.                          NMR MS  time                                               Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                        (M + 1)                                            (hr)                                               (%)    __________________________________________________________________________    46        2 #STR99##   8.8(1H, s), 7.5(1H, d), 7.4(2H,d), 7.1(2H, d), 5.2(2H,                     s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.8(3H, s), 3.0(1H,m), 2.9-2.7(2H, m), 2.7(3H,                     s),1.3(2H, m), 0.95(2H, m)                                    DMSO-d.sub.6                                        525 17 38    47        3 #STR100##  8.8(1H, s), 7.8(1H, d), 7.6(2H,d), 7.4(2H, d), 5.3(2H,                     s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.5(9H,                     s),1.3(2H, m), 0.95(2H, m)                                    DMSO-d.sub.6                                        551 17 34    48        4 #STR101##  8.8(1H, s), 7.8(1H, d), 7.5(2H,m), 7.2(2H, m), 5.2(2H,                     s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H,                     m),0.95(2H, m) DMSO-d.sub.6                                        513 17 40    49        5 #STR102##  8.8(1H, s), 8.3(2H, d), 7.8(1H,d), 7.7(2H, d), 5.4(2H,                     s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H,                     m),0.95(2H, m) DMSO-d.sub.6                                        540 17 37    50        6 #STR103##  8.8(1H, s), 8.0-7.5(5H, m), 5.4(2H, s), 4.6(2H, s),                     4.3(1H, m),4.1(1H, m), 3.9(1H, m), 3.0(1H,m),                     2.9-2.7(2H, m), 2.7(3H, s),1.3(2H, m), 0.95(2H,                                    DMSO-d.sub.6                                        520 17 42    51        7 #STR104##  8.8(1H, s), 7.8(1H, d), 7.0(3H,m), 6.2(2H, s), 5.2(2H,                     s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H, m),0.95                     (2H, m)        DMSO-d.sub.6                                        539 17 44    52        8 #STR105##  8.8(1H, s), 8.6(2H, m), 7.9(1H,d), 7.8(1H, d), 7.4(1H,                     q), 5.3(2H, s), 4.6(2H, s), 4.3(1H, m),4.1(1H, m),                     3.9(1H, m), 3.0(1H,m), 2.9-2.7(2H, m), 2.7(3H,                     s),1.3(2H, m), 0.95(2H, m)                                    DMSO-d.sub.6                                        496 17 30    53        9 #STR106##  8.8(1H, s), 7.6(1H, d), 7.6(2H,m), 6.5(1H, m), 5.1(2H,                     m), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m),3.9(1H, m),                     3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H, m),0.95                     (2H, m)        DMSO-d.sub.6                                        485 17 29    54        0 #STR107##  8.8(1H, s), 7.8(1H, d), 7.2(3H,m), 6.8(1H, s), 4.6(2H,                     s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m),3.0(1H, m),                     2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H,                                    DMSO-d.sub.6                                        571 20 27    55        1 #STR108##  8.8(1H, s), 8.3(1H, m), 8.0(1H,m), 7.8(1H, d), 7.5(1H,                     m), 5.7(2H, s), 4.6(2H, s), 4.3(1H, m),4.1(1H, m),                     3.9(1H, m), 3.0(1H,m), 2.9-2.7(2H, m), 2.7(3H,                     s),1.3(2H, m), 0.95(2H, m)                                    DMSO-d.sub.6                                        570 17 42    __________________________________________________________________________

EXAMPLE 56 Synthesis of5-amino-7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR109##

448 mg of5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 438 mg of the compound prepared in Preparation 8 were suspendedin 15 ml of acetonitrile and then 685 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas heated for 6 hours at 80° C. and 10 ml of water was added thereto.This suspension was filtered. The filtered solid product was washed withwater, acetonitrile and ethyl ether to obtain 395 mg (Yield: 53%) of thetitle compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.62(1H, 7.92(1H, d), 7.40(5H, m), 6.10(2H,bs), 5.13(2H, s), 4.73(2H, s), 4.15(1H, m), 3.95(1H, m), 3.82(1H, m),3.35(2H, m), 3.01(1H, m), 2.80(1H, m), 2.73(1H, m), 1.25-1.05(4H, m); MS(FAB, m/e): 498(M+H)

EXAMPLES 57 to 66

The same starting material as Example 56 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 56 to prepare the respective compounds listed inthe following Table 13.

                                      TABLE 13    __________________________________________________________________________    Examples 57 to 66    4 #STR110##                                        FAB,                                            Reac.    Examp.                          NMR MS  time                                               Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                        (M + 1)                                            (hr)                                               (%)    __________________________________________________________________________    57        2 #STR111##  8.4(1H, s), 7.4(2H, bs), 7.2(2H, d), 7.0(2H, d), 5.1(2H,                     s),4.6(2H, m), 4.2(1H, m), 3.9(1H,m), 3.8(3H, s),                     3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H,                                    DMSO-d.sub.6                                        528 10 59    58        3 #STR112##  8.4(1H, s), 7.5(2H, d), 7.4(2H,bs), 7.3(2H, d), 5.2(2H,                     s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m),3.7(1H, m),                     3.0(1H, m), 2.8-2.6(2H, m), 1.4(9H, s), 1.1(4H,                                    DMSO-d.sub.6                                        554 17 67    59        4 #STR113##  8.4(1H, s), 7.4(4H, m), 7.1(2H,m), 5.1(2H, s), 4.6(2H,                     m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m),3.0(1H, m),                     2.8-2.6(2H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        516 17 55    60        5 #STR114##  8.4(1H, s), 8.2(2H, d), 7.6(2H,d), 7.4(2H, bs), 5.3(2H,                     s), 4.6,(2H, m), 4.2(1H, m), 3.9(1H, m),3.7(1H, m),                     3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        543 17 56    61        6 #STR115##  8.4(1H, s), 7.9-7.4(6H, m), 5.3(2H, s), 4.6(2H, m),                     4.2(1H, m),3.9(1H, m), 3.7(1H, m), 3.0(1H,m),                     2.8-2.6(2H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        523 18 62    62        7 #STR116##  8.4(1H, s), 7.3(2H, bs), 7.0(3H, m), 6.2(2H, s), 5.2(2H,                     s),4.6(2H, m), 4.2(1H, m), 3.9(1H,m), 3.7(1H, m),                     3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        542 18 65    63        8 #STR117##  8.5(3H, m), 7.6(1H, d), 7.4(1H,q), 7.3(2H, bs), 5.3(2H,                     s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m),3.7(1H, m),                     3.0(1H, m), 2.8-2.62H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        499 17 52    64        9 #STR118##  8.4(1H, s), 7.5-7.4(4H, m), 6.5(1H, m), 5.0(2H, m),                     4.6(2H, m),4.2(1H, m), 3.9(1H, m), 3.7(1H,m), 3.0(1H,                     m), 2.8-2.6(2H,1.1(4H, s)                                    DMSO-d.sub.6                                        488 18 49    65        0 #STR119##  8.4(1H, s), 7.4(2H, bs), 7.1(3H, m), 6.7(1H, s), 4.6(2H,                     m),4.2(1H, m), 3.9(1H, m), 3.7(1H,m), 3.0(1H, m),                     2.8-2.6(2H,1.1(4H, s)                                    DMSO-d.sub.6                                        574 18 43    66        1 #STR120##  8.4(1H, s), 8.2(1H, m), 7.9(1H,m, 7.4(3H, m), 5.6(2H,                     s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m),3.7(1H, m),                     3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H, s)                                    DMSO-d.sub.6                                        573 17 65    __________________________________________________________________________

EXAMPLE 67 Synthesis of7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-(2,4-difluorophenyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid ##STR121##

806 mg of7-chloro-1(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylicacid and 438 mg of the compound prepared in Preparation 8 were suspendedin 15 ml of acetonitrile and then 913 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for one hour at room temperature, and after adding 15 ml ofwater, was then stirred for further 30 minutes and filtered. Thefiltered solid product was washed with water and acetonitrile to obtain524 mg (Yield: 65%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.82(1H, s), 8.21(1H, d), 7.85(1H, m),7.56(1H, m), 7.40(6H, m), 5.16(2H, s), 4.76(2H, s), 4.18(1H, m),3.94(1H, m), 3.81(1H, m), 3.34(2H, m), 3.04(1H, m), 2.82(1H, m),2.73(1H, m), 1.30-1.00(4H, m); MS (FAB, m/e): 538(M+H)

EXAMPLES 68 to 77

The same starting material as Example 67 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the saneprocedure as Example 67 to prepare the respective compounds listed inthe following Table 14.

                                      TABLE 14    __________________________________________________________________________    Examples 68 to 77    5 #STR122##                                        FAB,                                            Reac.    Examp.                          NMR MS  time                                               Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                        (M + 1)                                            (hr)                                               (%)    __________________________________________________________________________    68        2 #STR123##  8.9(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(3H,                     m), 7.1(2H, d), 5.2(2H, s), 4.3(2H, s),4.0(1H, m),                     3.9(1H, m), 3.8(3H,s), 3.0(1H, m), 2.8-2.6(2H,                                    DMSO-d.sub.6                                        568 20 78    69        3 #STR124##  8.9(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(2H, m), 7.3(2H,                     m), 5.2(2H, s), 4.3(2H, s), 3.9(11H, m),3.0(1H, m),                     2.8-2.6(2H, m), 1.5(9H, s)                                    DMSO-d.sub.6                                        594 10 80    70        4 #STR125##  8.9(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.4(2H,                     m), 7.3(1H, dd), 7.1(2H, m), 5.1(2H,s), 4.3(2H, s),                     4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H,                                    DMSO-d.sub.6                                        556 15 81    71        5 #STR126##  8.9(1H, s), 8.3(2H, d), 8.1(1H,d), 7.8(1H, m), 7.7(2H,                     d), 7.6(1H, dd), 7.3(1H, m,), 5.3(2H,s), 4.3(2H, s),                     4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H,                                    DMSO-d.sub.6                                        583 15 75    72        6 #STR127##  8.8(1H, s), 8.1(1H, d), 7.9-7.4(6H, m), 7.3(1H, dd),                     5.3(2H,s), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H,                     m), 2.8-2.6(2H, m)                                    DMSO-d.sub.6                                        563 15 80    73        7 #STR128##  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                     dd),7.0(3H, m), 6.2(2H, s), 5.1(2H,s), 4.3(21H, s),                     4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H,                                    DMSO-d.sub.6                                        582 15 87    74        8 #STR129##  8.8(1H, s), 8.6(1H, s), 8.5(1H,q), 7.8(2H, m), 7.6(1H,                     dd), 7.4(1H, q), 7.3(1H, dd), 5.2(2H,s), 4.3(2H, s),                     4.0(1H, m), 3.9(1H, m), 2.0(1H, m), 2.8-2.6(2H,                                    DMSO-d.sub.6                                        539 15 70    75        9 #STR130##  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.5(1H,                     d),7.45(1H, dd), 6.6(1H, m), 5.0(2H, m), 4.3(2H, s),                     4.0(1H, m),3.9(1H, m), 3.0(1H, m),2.8-2.6(2H,                                    DMSO-d.sub.6                                        528 10 69    76        0 #STR131##  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                     dd),7.1(3H, m), 6.7(1H, s), 4.3(2H,s), 4.0(1H, m),                     3.9(1H, m), 3.0(1H, m), 2.8-2,.6(2H, m)                                    DMSO-d.sub.6                                        614 20 59    77        1 #STR132##  8.8(1H, s), 8.2(1H, m), 8.1(1H,d), 8.0(1H, m), 7.8(1H,                     d), 7.6(1H, dd), 7.4(1H, m), 7.3(1H,dd), 5.6(2H, s),                     4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H,                     m),2.8-2.6(2H, m)                                    DMSO-d.sub.6                                        613 10 82    __________________________________________________________________________

EXAMPLE 78 Synthesis of7-(4-aminomethyl-3-benzyloxyiminopyrrolidin-1-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylicacid ##STR133##

353 mg of1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and380 mg of the compound prepared in Preparation 8 were suspended in 15 mlof acetonitrile and then 593 mg of 1,8-diazabicyclo5.4.0!undec-7-ene(DBU) was slowly added thereto. The reaction mixturewas stirred for 2.5 hours at 80° C., and after adding 15 ml of water,was then stirred for further 30 minutes under cold water bath andfiltered. The filtered solid product was washed with water, acetonitrileand ethyl ether to obtain 391 mg (Yield: 64%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.8(1H, s), 7.8(1H, d), 7.40(5H, m),5.10(2H,s), 4.6(2H, q), 4.4(2H, dd), 4.0(1H, m), 3.7(1H, m), 3.1(1H, m),2.8(2H, ddd), 1.46(3H, t); MS (FAB, m/e): 471(M+H)

EXAMPLES 79 to 88

The same starting material as Example 78 was reacted with each of thecompounds prepared in Preparations 19 to 28 according to the sameprocedure as Example 78 to prepare the respective compounds listed inthe following Table 15.

                                      TABLE 15    __________________________________________________________________________    Examples 79 to 88    8 #STR134##                                         FAB, Reac.    Examp.                          NMR  MS   time                                                 Yield    No. R            .sup.1 H NMR, δ(ppm)                                    solv.                                         (M + 1)                                              (min)                                                 (%)    __________________________________________________________________________    79        7 #STR135##  8.8(1H, s), 7.8(1H, d), 7.4(2H,d), 7.1(2H, d), 5.0(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),3.9(1H, m),                     3.7(3H, s), 3.1(1H,m), 2.9-2.7(2H, m), 1.45(3H,                                    DMSO-d.sub.6                                         501  4  73    80        8 #STR136##  8.8(1H, s), 7.8(1H, d), 7.4(2H,d), 7.2(2H, d), 5.1(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.1(1H, m),3.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t), 1.4(9H,                                    DMSO-d.sub.6                                         527  2.5                                                 77    81        9 #STR137##  8.8(1H, s) , 7.8(1H, d), 7.3(2H,m), 7.0(2H, m), 5.0(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),3.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         489  3  80    82        0 #STR138##  8.8(1H, s), 8.3(2H, d), 7.8(1H,d), 7.7(2H, d), 5.3(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),3.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         516  3  75    83        1 #STR139##  8.8(1H, s), 7.9-7.4(5H, m),5.3(2H, s), 4.5(2H, q),                     4.4(2H, s),4.2(1H, m), 3.9(1H, m), 3.1(1H,m),                     2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         496  3  80    84        2 #STR140##  8.8(1H, s), 7.8(1H, d), 6.8(3H,m), 6.0(2H, s), 5.0(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),3.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         515  4  69    85        3 #STR141##  8.8(1H, s), 8.6(2H, m), 7.8(2H,m), 7.4(1H, q), 5.3(2H,                     s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),3.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         471  2  70    86        4 #STR142##  8.8(1H, s), 7.8(1H, d), 7.5(2H,m), 6.5(1H, m), 5.0(2H,                     m), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m),2.9(1H, m),                     3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t)                                    DMSO-d.sub.6                                         461  2  67    87        5 #STR143##  8.8(1H, s), 7.8(1H, d), 7.1(3H,m), 6.7(1H, s), 4.5(2H,                     q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m),3.1(1H, m),                     2.9-2.7(2H, m),1.45(3H, t)                                    DMSO-d.sub.6                                         547  3.sup.-                                                 63    88        6 #STR144##  8.8(1H, s), 8.2(1H, m), 7.9(1H,m), 7.8(1H, d), 7.4(1H,                     m), 5.6(2H, s), 4.5(2H, q), 4.4(2H, s),4.2(1H, m),                     3.9(1H, m), 3.1(1H,m), 2.9-2.7(2H, m), 1.5(3H,                                    DMSO-d.sub.6                                         546  4  70    __________________________________________________________________________

EXAMPLE 89 Synthesis of7-(4-aminomethyl-3-t-butyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxlicacid ##STR145##

141 mg (0.5 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro1,8!naphthyridine-3-carboxylic acid and 143 mg (0.55 mmole) of4-aminomethyl-pyrrolidin-3-one t-butyloxime dihydrochloride werethoroughly suspended in 2.5 ml of acetonitrile. Then, 2.30mg (1.5 mmole)of 1,8-diazabicyclo 5.4.0!undec-7-ene was slowly added dropwise thereto.The reaction mixture was stirred for 30 minutes at room temperature, andafter adding 1 ml of water, was then vigorously stirred for 10 minutesand filtered. The filtered solid product was successively washed withacetonitrile-water (4:1 v/v, 2 ml) and acetonitrile (2 ml×2) and thenwith ether and dried to obtain 132mg (Yield: 61%) of the titlecompounds.

¹ H NMR (DMSO-d₆, ppm): δ 8.6(1H, s), 8.1(1H, d), 4.6(2H, s), 4.2(1H,dd), 3.9(1H, dd), 3.7(1H, m), 3.1(1H, dd), 2.9-2.7(2H, ddd), 1.3(9H, s),1.2 (2H, m), 1.1(2H, m); FAB MS (POS): 432 M+H!⁺

EXAMPLE 90 Synthesis of7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR146##

141 mg (0.5 mmole) of1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and 143 mg (0.55 mmole) of3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were refluxedfor 2.5 hours under heating according to the same manner as Example 89and cooled down to room temperature. Then, the resulting product wasthen separated and purified with preparative HPLC to obtain. 151 mg(Yield: 67%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.3(1H,m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.3(9H, s),1.15(4H, s); FAB MS(POS): 449 M+H!⁺

EXAMPLE 91 Synthesis of 8-chloro-1-cyclopropyl-6-fluoro-7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)!-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR147##

150 mg (0.5 mmole) of8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid was reacted according to the same manner as Example 90. Then, thereaction solution was concentrated and the residue was purified withpreparative HPLC to obtain 148 mg (Yield: 64%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.7(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(1H,m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3(9H, s),1.2-0.9(4H, m); FAB MS(POS): M+H!⁺ 465

EXAMPLE 92 Synthesis of7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxlicacid ##STR148##

132 mg (0.5 mmole) of1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acidwas refluxed for 3.5 hours under heating according to the same manner asExample 89. Then, the resulting residue was subjected to preparativeHPLC to obtain 129 mg (Yield: 60%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(2H,s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m),1.4(9H, s), 1.3-1.1(4H, m); FAB MS(POS): M+H!⁺ =431

EXAMPLE 93 Synthesis of5-amino-7-(3-aminomethyl-4t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR149##

148 mg (0.5 mmole) of5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid was refluxed for 8 hours under heating according to the same manneras Example 89. Then, the resulting residue was purified with preparativeHPLC to obtain 151 mg (Yield: 65%) of the title compound. ¹ H NMR(DMSO-d₆, ppm): δ 8.6(1H, s), 7.5(2H, br), 4.3 (2H, s), 4.0-3.8(3H, m),3.2(1H, m), 2.8-2.6(2H, m), 1.3 (9H, s), 1.1(4H, m); FAB MS(POS): M+H!⁺=464

EXAMPLE 94 Synthesis of7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxlicacid ##STR150##

148 mg (0.5 mmole) of1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylicacid was refluxed for 10 hours under heating according to the samemanner as Example 89. Then, the resulting residue was purified withpreparative HPLC to obtain 92 mg (Yield: 40%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.9(1H, s), 7.8(1H, d), 4.5(2H, s), 4.3(1H,m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.7(2H, m), 2.7(3H, s),1.3(9H, s), 1.25(2H, m), 0.9(2H, s); FAB MS(POS): M+H!⁺ =461

EXAMPLE 95 Synthesis of7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxlicacid ##STR151##

168 mg (0.5 mmole) of6,7-difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydro-naphthyridine-3-carboxylicacid and 143 mg (0.55 mmole) of3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride weresuspended in 3 ml of dry acetonitrile. Then, 230 mg (1.5 mmole) of1,8-diazabicyclo 5.4.0!undec-7-ene was added thereto, and the reactionmixture was stirred for 15 minutes at room temperature and then treatedaccording to the same manner as Example 89 to obtain 203 mg (Yield: 81%)of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.9(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H,dd), 7.3(1H, dd), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H, m),2.8-2.6(2H, m), 1.3(9H, s); FAB MS(POS): M+H!⁺ =504

EXAMPLE 96 Synthesis of7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-6,8-difluoro-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR152##

136 mg (0.5 mmole) of1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid wasrefluxed for 5 hours under heating according to the sane manner asExample 89. Then, the resulting residue was purified with preparativeHPLC to obtain 170 mg (Yield: 78%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.8(1H, s), 7.8(1H, d), 4.5(2H, q), 4.4(2H,s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t),1.3(9H, s); FAB MS(POS): M+H!⁺ =437

EXAMPLES 97 to 176

The amine compounds prepared in Preparations 41 to 50 were treatedaccording to the same procedure as Examples 89 to 96 to prepare therespective compounds 97 to 176 of which NMR and MS data are listed inthe following Tables 16 to 23.

                                      TABLE 16    __________________________________________________________________________    Examples 97 to 106    1 #STR153##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (min)                                            (%)    __________________________________________________________________________    97        2 #STR154##                  8.6(1H, s), 8.0(1H, d), 4.7(1H,m), 4.6(2H, s), 4.2(1H, m),                  3.9(1H, m), 3.7(1H, m), 3.0(1H, m),2.9-2.7(2H, m),                  1.2-1.0(4H,m) , 0.9(6H, d)                                 DMSO-d.sub.6                                     418 10 73    98        3 #STR155##                  8.6(1H, s), 8.05(1H, d), 4.8(1H, m), 4.7(2H, s), 4.2(1H,                  m),4.0(1H, m), 3.7(1H, m), 3.0(1H,m), 2.9-2.7(2H, m),                  2.2(2H, m),2.1(2H, m), 1.7(1H, m), 1.5(1H,m), 1.2-1.0(4H,                  m)             DMSO-d.sub.6                                     430 10 63    99        4 #STR156##                  8.6(1H, s), 8.0(1H, d), 4.7(1H,m), 4.5(2H, s), 4.2(1H, m),                  3.9(1H, m), 3.7(1H, m), 3.1(1H, m),2.9-2.8(2H, m), 1.7(4H,                  s), 1.6(2H, m), 1.5(2H, m), 1.2-1.0(4H, m)                                 DMSO-d.sub.6                                     444 50 77    100        5 #STR157##                  8.6(1H, s), 8.0(1H, d), 4.8(1H,m), 4.6(2H, s), 4.2(1H, m),                  3.9(1H, m), 3.8-3.6(5H, m), 3.1(1H, m), 2.9-2.7(2H, m),                  2.3-1.9(2H, m), 1.2-1.0(4H, m)                                 DMSO-d.sub.6                                     446 30 61    101        6 #STR158##                  8.65(1H, m), 8.05(1H, d), 4.6(2H, s), 4.25(1H, m),                  3.9(1H,m), 3.85,(2H, dd), 3.75(1H, m),3.1(1H, m),                  3.0-2.8(2H, m),1.3-1.0(5H, m), 0.5(2H, m),0.3(2H,                                 DMSO-d.sub.6                                     430 30 84    102        7 #STR159##                  8.6(1H, s), 8.0(1H, d), 4.6(2H, s), 4.2(1H, m), 3.55(1H,                  m), 3.8(2H, d), 3.7(1H, m), 3.05(1H,m), 2.9-2.7(2H, m),                  1.9(1H, m),1.2-1.0(4H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     432 15 80    103        8 #STR160##                  8.60(1H, s), 8.05(1H, d), 4.74(2H, s), 4.60(2H, s),                  4.21(1H,m), 3.97(1H, m), 3.75(1H, m),3.50(1H, s), 3.35(2H,                  s), 3.08(1H, m), 2.90-2.70(2H, m),1.30-1.05 (4H,                                 DMSO-d.sub.6                                     414 90 63    104        9 #STR161##                  8.6(1H, s), 8.0(1H, d), 4.6(2H,s), 4.2(1H, m), 4.1(2H, t),                  3.9(1H,m), 3.7(1H, m), 3.1(1H, m),2.9-2.7(2H, m), 2.8(1H,                  s), 2.5(2H, t), 1.2-1.0(4H, m)                                 DMSO-d.sub.6                                     428 15 85    105        0 #STR162##                  8.6(1H,s), 8.0(1H, d), 4.6(2H,s), 4.2(1H, m), 3.9(1H, m),                  3.7(1H, m), 3.4(2H, s), 3.3(3H, s),3.0(1H, m), 2.8-2.6(2H,                  m),1.2-1.0(4H, m)                                 DMSO-d.sub.6                                     420 20 52    106        1 #STR163##                  8.6(1H, s), 8.05(1H, d), 4.6(2H, s), 4.3(2H, t), 4.2(1H,                  m),3.9(1H, m), 3.8(2H, t), 3.7(1H,m), 3.1(1H, m),                  2.9-2.7(2H, m),1.2-1.0(4H, m)                                 DMSO-d.sub.6                                     438 10 50    __________________________________________________________________________

                                      TABLE 17    __________________________________________________________________________    Examples 107 to 116    2 #STR164##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (min)                                            (%)    __________________________________________________________________________    107        2 #STR165##                  8.8(1H, s), 7.8(1H, d), 4.7(1H,m), 4.5(2H, s), 4.1(1H, m),                  3.9(1H, m), 3.8(1H, m), 2.9(1H, m),2.8-2.7(2H, m), 1.15(4H,                  s),0.9(6H, d)  DMSO-d.sub.6                                     435 2  69    108        3 #STR166##                  8.8(1H, s), 7.8(1H, d), 4.8(1H,m), 4.4(2H, s), 4.1(1H, m),                  3.9(1H, m), 3.8(1H, m), 2.9(1H, m),2.8-2.7(2H, m), 2.2(2H,                  m), 2.1(2H, m), 1.7(1H, m), 1.5(1H, m),1.15 (4H,                                 DMSO-d.sub.6                                     447 2  61    109        4 #STR167##                  8.8(1H, s), 7.8(1H, d), 4.7(1H,m), 4.5(2H, s), 4.1(1H, m),                  3.9(1H, m), 3.8(1H, m), 2.9(1H, m),2.8-2.7(2H, m), 1.7(4H,                  s), 1.6(2H, m), 1.5(2H, m), 1.15(2H,m), 1.0(2H, m)    110        5 #STR168##                  8.8(1H, s), 7.8(1H, d), 4.8(1H,m), 4.5(2H, s), 4.1(1H, m),                  3.9(1H, m), 3.8-3.6(4H, m), 3.1(1H, m), 2.8-2.7(2H, m),                  2.3-1.9(2H, m), 1.2-1.0(4H, s)                                 DMSO-d.sub.6                                     461 2  63    111        6 #STR169##                  8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.1(1H, m), 3.9(1H,                  m),3.8(2H, dd), 3.75(1H, m), 3.1(1H, m), 2.8-2.7(2H, m),                  1.15(4H, m), 1.05(1H, m), 0.5(2H,m), 0.3(2H,                                 DMSO-d.sub.6                                     463 2  54    112        7 #STR170##                  8.8(1H, s), 7.8(1H, d), 4.5(2H,s), 4.1(1H, m), 3.9(1H, m),                  3.8(2H, d), 3.75(1H, m), 3.0(1H,m), 2.8-2.7(2H, m), 1.9(1H,                  m),1.2-1.0(4H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     449 2  64    113        8 #STR171##                  8.8(1H, s), 7.8(1H, d), 4.62(2H, s), 4.3(2H, s), 4.1(1H,m),                  3.9(1H, m), 3.8(1H, m), 3.5(1H, s), 2.9(1H, m), 2.8-2.7(2H,                  m), 1.15(4H, m)                                 DMSO-d.sub.6                                     431 4  55    114        9 #STR172##                  8.8(1H, s), 7.8(1H, d), 4.5(2H,s), 4.1(1H, m), 4.0(2H, t),                  3.9(1H, m), 3.8(1H, m), 3.1(1H, m),2.8-2.7(2H, m), 2.7(1H,                  s), 2.5(2H, t), 1.2(4H, m)                                 DMSO-d.sub.6                                     445 2  65    115        0 #STR173##                  8.8(1H, s), 7.8(1H, d), 4.5(2H,s), 4.1(1H, m), 3.9(1H, m),                  3.8(1H, m), 3.3(2H, s), 3.1(3H, s),3.0(1H, m), 2.8-2.7(2H,                  m),1.15(4H, m) DMSO-d.sub.6                                     437 1.5                                            47    116        1 #STR174##                  8.8(1H, s), 7.8(1H, d), 4.5(2H,s), 4.3(2H, t), 4.1(1H, m),                  3.9(1H, m), 3.8(2H, t), 3.75(1H,m), 3.0(1H, m), 2.8-2.7(2H,                  m),1.15(4H, m) DMSO-d.sub.6                                     455 1.5                                            53    __________________________________________________________________________

                                      TABLE 18    __________________________________________________________________________    Examples 117 to 126    3 #STR175##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (hr)                                            (%)    __________________________________________________________________________    117        2 #STR176##                  8.8(1H, s), 7.9(1H, d), 4.7(1H, m), 4.4(2H, s), 4.3(1H, m),                  3.8(1H, m), 3.7(1H, m), 3.0(1H, m),2.9-2.7(2H, m),                  1.80-0.9(4H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     451 2.5                                            68    118        3 #STR177##                  8.8(1H, s), 7.9(1H, d), 4.7(1H,m), 4.4(2H, s), 4.3(1H, m),                  3.8(1H, m), 3.7(1H, m), 3.0(1H, m),2.5-2.7(2H, m), 2.2(2H,                  m),2.1(2H, m), 1.7(1H, m), 1.5(1H,m), 1.12-0.9(4H,                                 DMSO-d.sub.6                                     463 2  61    119        4 #STR178##                  8.8(1H, s), 7.9(1H, d), 4.7(1H,m), 4.4(2H, s), 4.3(1H, m),                  3.8(1H, m), 3.7(1H, m), 3.0(1H, m),2.9-2.7(2H, m), 1.7(4H,                  s), 1.6(2H, m), 1.5(2H, m), 1.2-0.9(4H, m)                                 DMSO-d.sub.6                                     477 2  55    120        5 #STR179##                  8.8(1H, s), 7.9(1H, d), 4.8(1H,m), 4.4(2H, s), 4.3(1H, m),                  3.8-3.6(6H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.3-1.9(2H, m),                  1.2-0.9(4H, m) DMSO-d.sub.6                                     479 2.5                                            49    121        6 #STR180##                  8.8(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(1H, m), 3.8-3.7(4H,                  m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(5H, m), 0.5(2H, m),                  0.3(2H, m)     DMSO-d.sub.6                                     463 2  52    122        7 #STR181##                  8.8(1H, s), 7.9(1H, d), 4.4(2H,s), 4.3(1H, m), 3.8-3.7(4H,                  m),3.0(1H, m), 2.9-2.7(2H, m),1.9(1H, m), 1.2-0.9(4H,                  m),0.9(6H, d)  DMSO-d.sub.6                                     465 2  60    123        8 #STR182##                  8.8(1H, s), 7.9(1H, d), 4.61(2H, s), 4.4(2H, s), 4.3(1H,m),                  3.8(1H, m), 3.5(1H, s),3.0(1H, m), 2.9-2.7(2H,                  m),1.2-0.9(4H, m)                                 DMSO-d.sub.6                                     447 2  62    124        9 #STR183##                  8.8(1H, s), 7.9(12H, d), 4.4(2H,s), 4.3(1H, m), 4.1(2H, t),                  3.8(1H, m), 3.7(1H, m), 3.0(1H, m),2.9-2.7(2H, m), 2.8(1H,                  s), 2.5(2H, t), 1,2-0.9(4H, m)                                 DMSO-d.sub.6                                     461 2.5                                            57    125        0 #STR184##                  8.8(1H, s), 7.9(1H, d), 4.4(2H,s), 4.3(1H, m), 3.8(1H, m),                  3.7(1H, m), 3.3(2H, s), 3.1(3H, s),3.0(1H, m), 2.9-2.7(2H,                  m),1.2-0.9(4H, m)                                 DMSO-d.sub.6                                     453 1.5                                            51    126        1 #STR185##                  8.8(1H, s), 7.9(1H, d), 4.4(2H,s), 4.3(3H, m), 3.8-3.7(4H,                  m),3.0(1H, m), 2.9-2.7(2H, m),1.2-0.9(4H,                                 DMSo-d.sub.6                                     471 2  64    __________________________________________________________________________

                                      TABLE 19    __________________________________________________________________________    Examples 127 to 136    4 #STR186##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (hr)                                            (%)    __________________________________________________________________________    127        2 #STR187##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.6(1H, m), 4.4(2H, s),                  3.9(1H, m), 3.8(1H, m), 3.7(1H, m),3.0(1H, m), 2.9-2.7(2H,                  m),1.3-1.1(4H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     417 3  55    128        3 #STR188##                  8,6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.7(1H, m), 4.4(2H,                  s),3.9(1H, m), 3.8(1H, m), 3.0(1H,m), 2.9-2.7(2H, m),                  2.2(2H, m),2.1(2H, m), 1.7(1H, m), 1.5(2H,m), 1.3-1.1(4H,                  m)             DMSO-d.sub.6                                     429 3  52    129        4 #STR189##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.7(1H, m), 4.4(2H, s),                  3.9(1H, m), 3.8(1H, m), 3.7(1H, m),3.0(1H, m), 2.9-2.7(2H,                  m), 1.7(4H, s), 1.6(2H, m), 1.5(2H, m),1.3-1.1(4H,                                 DMSO-d.sub.6                                     443 3  59    130        5 #STR190##                  8,6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.8(1H, m), 4.4(2H, s),                  3.9(1H, m), 3.8-3,6(6H, m), 3.0(1H, m), 2.9-2.7(2H, m),                  2.3-1.9(2H, m), 1.3-1.1(4H, m)                                 DMSO-d.sub.6                                     445 3  45    131        6 #STR191##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.6(1H, m), 4.4(2H, s),                  3.9(1H, m), 3.8-3.7(3H, m), 3.1(1H, m), 2.9-2.7(2H, m),                  1.3-1.1(4H, m), 1.0(1H, m), 0.5(2H,m), 0.3(2H,                                 DMSO-d.sub.6                                     429 3  57    132        7 #STR192##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.4(2H, s), 3.9(1H, m),                  3.8(3H, m), 3.7(1H, m), 3.1(1H, m),2.9-2.7(2H, m), 1.9(1H,                  m),1.3-1.1(4H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     431 3  76    133        8 #STR193##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.6(2H, s), 4.4(2H, s),                  3.9(1H, m), 3.8(1H, m), 3.7(1H, m),3.5(1H, s), 3.0(1H, m),                  2.9-2.7(2H, m), 1.3--1.1(4H, m)                                 DMSO-d.sub.6                                     413 3  49    134        9 #STR194##                  8.,6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.4(2H, s), 4.1(2H, t),                  3.9(1H, m), 3.8(1H, m), 3.7(1H, m),3.1(1H, m), 2.9-2.7(2H,                  m),2.8(1H, s), 2.5(2H, t), 1.3-1.1(4H, m)                                 DMSO-d.sub.6                                     427 3  59    135        0 #STR195##                  8,6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.4(2H, s), 4.1(2H, t),                  3.9(1H, m), 3.8(1H, m), 3.7(1H, m),3.3(2H, s), 3.2(3H, s),                  3.0(1H,m), 2.9-2.7(2H, m), 1.3-1.1(4H, m)                                 DMSO-d.sub.6                                     419 1.5                                            47    136        1 #STR196##                  8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.4(2H, s), 4.3(2H, t),                  3.9(1H, m), 3.8(3H, m), 3.7(1H, m),3.0(1H, m), 2.9-2.7(2H,                  m),1.3-1.1(4H, m)                                 DMSO-d.sub.6                                     437 2  53    __________________________________________________________________________

                                      TABLE 20    __________________________________________________________________________    Examples 137 to 146    5 #STR197##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (hr)                                            (%)    __________________________________________________________________________    137        2 #STR198##                  8.8(1H, s), 7.8(1H, d), 4.7(1H,m), 4.5(2H, s), 4.3(1H, m),                  4.1(1H, m), 3.9(1H, m), 3.0(1H, m),2.8-2.7(2H, m), 2.65(3H,                  s),1.3(2H, m), 1.0(2H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     447 9  57    138        3 #STR199##                  8.8(1H, s), 7.8(1H, d), 4.8(1H,m), 4.7(2H, s), 4.3(1H, m),                  4.2(1H, m), 3.9(1H, m), 3.0(1H, m),2.9-2.7(2H, m), 2.7(3H,                  s), 2.2(2H, m), 2.1(2H, m), 1.6(1H, m),1.5(1H, m), 1.3(2H,                  m), 0.95(2H, m)                                 DMSO-d.sub.6                                     459 12 65    139        4 #STR200##                  8.8(1H, s), 7.8(1H, d), 4.7(1H,m), 4.5(2H, s), 4.3(1H, m),                  4.2(1H, m), 3.9(1H, m), 3.1(1H, m),2.9-2.8(2H, m), 2.7(3H,                  s), 1.7(4H, s), 1.6(2H, m), 1.5(2H, m),1.3(2H, m), 0.9(2H,                  m)             DMSO-d.sub.6                                     473 12 63    140        5 #STR201##                  8.8(1H, s), 7.8(1H, d), 4.8(1H,m), 4.6(2H, s), 4.3(1H, m),                  4.2(1H, m), 4.0(1H, m), 3.8-3.6(4H, m), 3.1(1H, m),                  2.9-2.7(2H, m), 2.7(3H, s), 2.3-1.9(2H, m), 1.3(2H, m),                  0.9(2H, m)     DMSO-d.sub.6                                     475 12 42    141        6 #STR202##                  8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.3(1H, m), 3.9(1H,                  m),3.85(2H, dd), 3.1(1H, m), 3.0-2.8(2H, m), 2.7(3H, s),                  1.3(2H,m), 1.1(1H, m), 0.9(2H, m),0.5(2H, m), 0.3(2H,                                 DMSO-d.sub.6                                     459 12 63    142        7 #STR203##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.3(1H, m), 4.2(1H, m),                  3.95(1H, m), 3.8(2H, d), 3.05(1H,m), 2.9-2.7(2H, m),                  2.7(3H, s),1.9(1H, m), 1.3(2H, m), 1.0(2H,m), 0.9(6H,                                 DMSO-d.sub.6                                     443 12 68    143        8 #STR204##                  8.8(1H, s), 7.8(1H, d), 4.62(2H, s), 4.60(2H, s),                  4.3(1H,m), 4.1(1H, m), 3.9(1H, m), 3.5(1H, s), 3.0(1H, m),                  2.7(3H, s),2.9-2.7(2H, m), 1.3(2H, m),1.0(2H,                                 DMSO-d.sub.6                                     443 12 30    144        9 #STR205##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.3(1H, m), 4.2(1H,                  m),4.15(2H, t), 3.1(1H, m), 2.9-2.7(2H, m), 2.8(1H, s),                  2.7(3H,s), 2.5(3H, t), 1.3(2H, m),0.9(2H,                                 DMSO-d.sub.6                                     457 12 52    145        0 #STR206##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.3(1H, m), 4.15(1H, m),                  3.9(1H, m), 3.3(2H, s), 3.1(3H, s),2.9(1H, m), 2.8-2,6(2H,                  m),2.7(2H, s), 1.3(2H, m),0.9(2H, m)                                 DMSO-d.sub.6                                     449 8  39    146        1 #STR207##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.3(2H, t), 4.25(1H, m),                  4.2(1H, m), 3.9(1H, m), 3.8(2H, t),2.9-2.7(2H, m), 2.7(3H,                  s), 1.3(2H, m), 1.0(2H, m)                                 DMSO-d.sub.6                                     467 12 57    __________________________________________________________________________

                                      TABLE 21    __________________________________________________________________________    Examples 147 to 156    1 #STR208##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (hr)                                            (%)    __________________________________________________________________________    147        2 #STR209##                  8.4(1H, s), 7.7(2H, br), 4.5(1H, m), 4.3(2H, s),                  4.0-3.8(3H, m), 3.2(1H, m), 2.8-2.6(2H, m), 1.1(4H, s),                  0.9(6H, d)     DMSO-d.sub.6                                     450 5  73    148        3 #STR210##                  8.3(1H, s), 7.3(2H, br), 4.8(1H, m), 4.3(2H, s),                  4.0-3.8(3H, m), 2.8-2.6(2H, m), 2.2(2H, m), 2.1(2H, m),                  1.6(1H, m),1.5(1H, m), 1.1(4H, m)                                 DMSO-d.sub.6                                     462 8  64    149        4 #STR211##                  8,4(1H, s), 7.4(2H, br), 4.7(1H, m), 4.5(2H, s), 4.2(1H,                  m),3.9(1H, m), 3.7(1H, m), 3.0(1H,m), 2.8-2.6(2H, m),                  1.7(4H, s),1.6(2H, m), 1.5(2H, m), 1.1(4H,                                 DMSO-d.sub.6                                     476 8  61    150        5 #STR212##                  8.4(1H, s), 7.4(2H, br), 4.8(1H, m), 4.6(2H, s), 4.2(1H,                  m),4.0(1H, m), 3.8-3.6(4H, m),3.0(1H, m), 2.8-2.6(2H,                  m),2.3-1.9(2H, m), 1.2-0.9(4H, m)                                 DMSO-d.sub.6                                     478 12 54    151        6 #STR213##                  8.4(1H, s), 7.5(2H, br), 4.6(2H, s), 3.9(1H, m),                  3.8(2H,dd), 3.0(1H, m), 2.9-2.8(2H,m), 1.0(1H, m), 0.5(2H,                  m),0.3(2H, m)  DMSO-d.sub.6                                     462 5  82    152        7 #STR214##                  8.4(1H, s), 7.5(2H, br), 4.5(2H, s), 3.9(1H, m),                  3.8(2H,dd), 3.1(1H, m), 2.9-2.7(2H,m), 1.9(1H, m),                  1.2-1.1(4H, m),0.9(6H, d)                                 DMSO-d.sub.6                                     464 6  75    153        8 #STR215##                  8.4(1H, s), 7.4(2H, br), 4.6(2H, s), 4.59(2H, m),                  4.2(1H,m), 3.9(1H, m), 3.7(1H, m), 3.5(1H, s), 3.0(1H, m),                  2.8-2.6(2H, m), 1.1(4H, s)                                 DMSO-d.sub.6                                     446 4  50    154        9 #STR216##                  8.4(1H, s), 7.5(2H, br), 4.4(2H, s), 4.1(1H, m), 4.0(2H,                  t),3.9(1H, m), 3.8(1H, m), 3.1(1H,m), 2.8-2.7(2H, m),                  2.8(1H, s),2.5(2H, t), 1.2-0.9(4H, m)                                 DMSO-d.sub.6                                     460 5  70    155        0 #STR217##                  8.4(1H, s), 7.4(2H, br), 4.4(2H, s), 4.3(2H, t), 4.1(1H,                  m),3.9(1H, m), 3.7(2H, t), 3.6(1H,m), 3.3(2H, s), 3.0(3H,                  s), 2.9(1H, m), 2.8-2.6(2H, m),1.3-0.9(4H,                                 DMSO-d.sub.6                                     452 3  60    156        1 #STR218##                  8.4(1H, s), 7.4(2H, br), 4.4(2H, s), 4.3(2H, t), 4.0(2H,                  m),3.9(1H, m), 3.8(2H, t), 3.7(1H,m), 3.2(1H, m),                  2.9-2.7(2H, m),1.1(4H, s)                                 DMSO-d.sub.6                                     470 5  72    __________________________________________________________________________

                                      TABLE 22    __________________________________________________________________________    Examples 157 to 166    2 #STR219##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (min)                                            (%)    __________________________________________________________________________    157        2 #STR220##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.6(1H, m), 4.3(2H, s), 4.0(1H,m), 3.9(1H, m), 3.0(1H,                  m),2.8-2.6(2H, m), 0.9(6H, d)                                 DMSO-d.sub.6                                     490 15 64    158        3 #STR221##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.7(1H, m), 4.4(2H, s), 4.0(1H,m), 3.9(1H, m), 3.0(1H,                  m), 2.8-2.6(2H, m), 2.2(2H, m), 2.1(2H,m), 1.7(1H, m),                  1.5(1H, m)     DMSO-d.sub.6                                     502 20 61    159        4 #STR222##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.7(1H, m), 4.4(2H, s), 4.0(1H,m), 3.9(1H, m), 3.0(1H,                  m), 2.8-2.6(2H, m), 2.2(2H, m), 2.1(2H,m), 1.7(1H, m),                  1.5(1H, m)     DMSO-d.sub.6                                     516 35 70    160        5 #STR223##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.8(1H, m), 4.4(2H, s), 4.0(1H,m), 3.9(1H, m),                  3.8-3.6(4H,m), 3.0(1H, m), 2.9-2.6(2H,m), 2.3-1.9(2H,                                 DMSO-d.sub.6                                     518 35 55    161        6 #STR224##                  8.8(1H, s), 8.1(1H, d), 7.8(1H, dd), 7.6(1H, dd),                  7.3(1H,dd), 4.6(2H, s), 4.2(1H, m),3.9(1H, m), 3.8(2H, dd),                  3.0(1H, m), 2.8-2.6(2H, m), 1.1(1H, m), 0.5(2H, m), 0.3(2H,                  m)             DMSO-d.sub.6                                     502 30 65    162        7 #STR225##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,dd), 7.6(1H, dd) , 7.3(1H,                  dd),4.6(2H, s), 4.0(1H, m), 3.9(1H,m), 3.8(2H, d), 3.0(1H,                  m),2.8-2.6(2H, m), 1.9(1H, m),0.9(6H, d)    163        8 #STR226##                  8.79(1H, s), 8.01(1H, d), 7.8(1H, m), 7.6(1H, dd),                  7.3(1H,dd), 4.73(2H, s), 4.61(2H, s),4.21(1H, m), 3.75(1H,                  m), 3.50(1H, s), 3.35(2H, s), 3.08(1H,m), 2.90-2.70(2H,                                 DMSO-d.sub.6                                     486 60 52    164        9 #STR227##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.6(2H, s), 4.1(1H, m), 4.0(2H,t), 3.9(1H, m), 3.0(1H,                  m),2.8-2.6(2H, m), 2.7(1H, s),2.5(2H, t)                                 DMSO-d.sub.6                                     500 25 53    165        0 #STR228##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H,                  dd),4.6(2H, s), 4.1(1H, m), 3.9(1H,m), 3.3(2H, s), 3.1(3H,                  s), 3.0(1H, m), 2.8-2.6(2H, m)                                 DMSO-d.sub.6                                     492 30 47    166        1 #STR229##                  8.8(1H, s), 8.1(1H, d), 7.8(1H,m), 7.6(1H, dd), 7.3(1H, m),                  4.6(2H, s), 4.3(2H, t), 4.1(1H, m),3,.9(1H, m), 3.8(2H, t),                  3.1(1H,m), 2.8-2.6(2H, m)                                 DMSO-d.sub.6                                     510 15 51    __________________________________________________________________________

                                      TABLE 23    __________________________________________________________________________    Examples 167 to 176    3 #STR230##                                     FAB,                                         Reac.    Examp.                       NMR MS  time                                            Yield    No. R         .sup.1 H NMR, δ(ppm)                                 solv.                                     (M + 1)                                         (hr)                                            (%)    __________________________________________________________________________    167        2 #STR231##                  8.8(1H, s), 7.8(1H, d), 4.6(1H,m), 4.5(2H, q), 4.4(2H, s),                  4.2(1H, m), 3.9(1H, m), 3.1(1H, m),2.9-2.7(2H, m), 1.45(3H,                  t),0.9(6H, d)  DMSO-d.sub.6                                     423 4.5                                            82    168        3 #STR232##                  8.8(1H, s), 7.8(1H, d), 4.7(1H,m), 4.5(2H, q), 4.4(2H, s),                  4.2(1H, m), 4.1(1H, m), 3.1(1H, m),2.9-2.7(2H, m), 2.2(2H,                  m), 2.1(2H, m), 1.7(1H, m), 1.6(1H, m),1.45(3H,                                 DMSO-d.sub.6                                     435 5  73    169        4 #STR233##                  8.8(1H, s), 7.8(1H, d), 4.75(1H, m), 4.6(2H, s), 4.5(2H,                  q),4.2(1H, m), 3.9(1H, m), 3.0-2.7(2H, m), 1.8(4H, s),                  1.65(2H,s), 1.5(2H, s), 1.4(3H, t)                                 DMSO-d.sub.6                                     449 5  77    170        5 #STR234##                  8.7(1H, s), 7.8(1H, d), 4.8(1H,m), 4.55(2H, s), 4.5(2H,                  dd),4.15(1H, m), 3.85(1H, m), 3.7(2H, m), 3.1(1H, m),                  2.9-2.7(2H, m), 2.1-1.9(2H, m), 1.5(3H, t)                                 DMSO-d.sub.6                                     451 6  71    171        6 #STR235##                  8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.45(2H, m),                  4.25(1H,m), 3.9(2H, dd), 3.7(1H, m),3.1(1H, m), 1.45(3H,                  t), 0.5(2H, m), 0.25(2H, m)                                 DMSO-d.sub.6                                     435 5  84    172        7 #STR236##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.5(2H, q), 4.2(1H, m),                  3.9(1H, m), 3.85(2H, dd), 3.1(1H,m), 2.9-2.7(2H, m),                  1.9(1H, m),0.9(6H, d)                                 DMSO-d.sub.6                                     437 4  70    173        8 #STR237##                  8.8(1H, s), 7.8(1H, d), 4.62(2H, s), 4.5(2H, q), 4.4(2H,                  s),4.2(1H, m), 3.9(1H, m), 3.5(1H,s), 3.1(1H, m),                  2.9-2.7(2H, m),1.45(3H, t)                                 DMSO-d.sub.6                                     419 3  50    174        9 #STR238##                  8.8(1H, s), 7.8(1H, d), 4.5(2H,dd), 4.2(1H, m), 4.15(2H,                  t),3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 2.8(1H, s),                  2.5(2H,t), 1.5(3H, t)                                 DMSP-d.sub.6                                     433 4.5                                            72    175        0 #STR239##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.5(2H, dd), 4.15(1H,                  m),3.9(1H, m), 3.3(2H, s), 3.1(3H,s), 2.9(1H, m), 2.8(1H,                  m), 2.6(1H, m), 1.5(3H, t)                                 DMSO-d.sub.6                                     425 2  39    176        1 #STR240##                  8.8(1H, s), 7.8(1H, d), 4.6(2H,s), 4.5(2H, dd), 4.3(2H, t),                  4.2(1H, m), 3.9(1H, m), 3.8(2H, t),2.9-2.7(2H, m), 1.5(3H,                  t)             DMSO-d.sub.6                                     443 2  57    __________________________________________________________________________

EXAMPLE 177 Synthesis of7-(4-amino-3-methoxyimino-pyrrolidin-1-yl)-1-cyclo-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR241##

2.33 g (10 mmole) of1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihyroquinoline-3-carboxylicacid and 4.27 g (11.5 mmole) of 4-aminomethyl-pyrrolidin-3-oneO-methyloxine ditrifluoroacetate were added to 23 ml of dryacetonitrile. Then, 4.6 g (30 mmole) of 1,8-diazabicyclo5.4.0!undec-7-ene was added thereto and the mixture was refluxed for 1.5hours under heating and then cooled down to room temperature. 15 ml ofdistilled water was added to the reaction solution. The precipitatedsolid product was separated and dried to obtain 2.24 g (Yield: 55%) ofthe title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.6(1H, s), 7.75(1H, d), 4.35(2H, s),4.1-3.9(2H, m), 3.8(3H, s), 3.7(1H, m), 3.35(1H, m), 2.9-2.6(2H, m),1.25 (2H, d), 0.95(2H, s); FAB MS (POS): M+H!=407

EXAMPLE 178 Synthesis of7-(4-aminomethyl-3-methoxyiminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR242##

141 mg (0.5 mmole) of1-cyclopropyl-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and 205 mg (0.55 mmole) of 4-aminoethylpyrrolidin-3-oneO-methyloxime ditrifluoroacetate were reacted for one hour according tothe same manner as Example 177. Then, the reaction solution wasconcentrated and the residue was purified with preparative HPLC toobtain 88 mg (Yield: 42%) co the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.7(1H, s), 7.85(1H, d), 4.4(1H, m), 3.75(3H,s), 3.7(3H, m), 3-4(2H, m), 3.0-2.7(2H, m), 1.25(2H, d), 1.0(2H, s); FABMS (POS): M+H!=423

EXAMPLE 179 Synthesis of7-(4-aminomethyl-3-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR243##

132 mg (0.5 mmole) of1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acidand 205 mg (0.55 mmole) of 4-aminomethylpyrrolidin-3-one O-methyloximeditrifluoroacetate were reacted for 3 hours according to the same manneras Example 177. Then, the reaction solution was concentrated and theresidue was purified with preparative HPLC to obtain 73 mg (Yield: 37%)of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.6(1H, s), 7.85(1H, d), 7.2(1H, d), 4.4(2H,d), 3.9(1H, m), 3.85(3H, s), 3.8-3.65(2H, m), 3.0(1H, m), 2.9-2.7(2H,m), 1.3(2H, m), 1.1(2H, m); FAB MS(POS): M+H!=389

EXAMPLE 180 Synthesis of7-(4-aminomethyl-3-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro1,8!naphthyridine-3-carboxyic acid ##STR244##

141 mg (0.5 mmole) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro1,8!naphthyridine-3-carboxylic acid and 205 mg (0.5 mmole) of4-aminomethylpyrrolidin-3-one O-methyloxime ditrifluoroacetate werereacted for 0.5 hour according to the same manner as Example 177 toobtain 167 mg (Yield: 85%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.6(1H, s), 8.05(1H, d), 4.55(2H, s), 4.3(1H,m), 3.85(3H, s, 1H, m), 3.7(1H, m), 3.1-3.0(2H, m), 1.2-1.0(4H, m); FABMS(POS): M+H!=390

EXAMPLE 181 Synthesis of7-(4-aminomethyl-3-methoxyiminonprrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro1,8!naphthyridine-3-carboxylic acid ##STR245##

177 mg (0.5 mmole) of1-(2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro1,8!naphthyridine-3-carboxylic acid and 205 mg (0.55 mmole) of4-aminomethylpyrrolidin-3-one O-methyloxime ditrifluoroacetate werereacted for 0.5 hour according to the same manner as Example 177 toobtain 59 mg (Yield: 25%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.85(1H, s), 8.05(1H, d), 7.75(1H, dd),7.6(1H, dd), 7.35(1H, dd), 4.3(2H, m), 3.8(3H, s, 1H, m), 3.6(1H, m),3.0 (1H, m), 2.7(2H, m); FAB MS(POS): M+H!=462

EXAMPLE 182 Synthesis of1-cyclopropyl-5-amino-6,8-difluoro-7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylicacid ##STR246##

143 mg (0.5 mmole) of1-cyclopropyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylicacid and 205 mg (0.55 mmole) of 4-aminomethylpyrrolidin-3-oneO-methyloxime ditrifluorcacetate were refluxed for 4 hours under heatingaccording to the same manner as Example 177. Then, the reaction solutionwas concentrated and the residue was purified with preparative HPLC toobtain 84 mg (Yield: 40%) of the title compound.

¹ H NMR (DMSO-d₆, ppm): δ 8.49(1H, s), 7.28(2H, bs), 4.3(2H, s), 3.9(2H,m), 3.8(3H, s), 3.7(1H, m), 2.6-2.8(3H, m), 1.05(4H, m); FAB MS(POS):M+H!⁺ =422

EXAMPLES 183 TO 202

The compounds prepared in Preparations 40 and 55 to 57 were treatedaccording to the same procedure as Example 177 to 182 to prepare therespective compounds 183 to 202 of which NMR and MS data are listed inthe following Table 24.

                                      TABLE 24    __________________________________________________________________________    Examples 183 to 202    4 #STR247##                                         FAB MS                                              Reac.    Ex.                  .sup.1 H NMR(DMSO-d.sub.6)                                         (POS)                                              Time                                                 Yield    No.       Q  R.sub.1     R.sub.2                         δ(ppm)     M + H!                                              (hr)                                                 (%)    __________________________________________________________________________    183       CF          5 #STR248## H  8.8(1H, s), 7.9(1H, d), 4.35(1H,m), 3.8(2H, m),                         3.7(2H, m), 3.4(1H, m), 3.0(2H, m), 1.2-1.0(4H,                                         393  2.5                                                 41    184       CF          5 #STR249## Et 8.8(1H, s), 7.9(1H, d), 4.4(1H,m), 4.2(2H, q),                         4.1-3.9(2H, m),3.4(2H, m), 2.8(2H, m), 1.4(3H,t),                         1.25-1.0(4H, m) 421  2  38    185       CF          5 #STR250## Ph 8.8(1H, s), 7.9(1H, d), 7.3-7.1(5H, m), 4.3(1H, m),                         3.9-3.7(3H,m), 3.4(2H, m), 2.8(2H, m), 1.2(2H, d),                         1.05(2H, s)     469  4  29    186       CF          5 #STR251## tBu                         8,8(1H, s), 7.9(1H, d), 4.35(1H,d), 4.1-3.9(3H, m),                         3.4(2H, m),2.9-2.7(2H, m), 1.35(9H, s),1.2-0.95(4H,                         m)              449  2  35    187       CCl          5 #STR252## H  8.9(1H, s), 7.9(1H, d), 4.4(1H,m), 3.8(2H, m),                         3.7(2H, m), 3.4(1H, m), 2.9(2H, m), 1.25(2H,                         m),1.1(2H, s)   409  1.5                                                 39    188       CCl          5 #STR253## Et 8.9(1H, s), 7.9(1H, d), 4.35(1H, m), 4.2(2H, q),                         3.95-3.75(3H, m), 3.7(2H, m), 3.4(2H,                         m),2.85-2.7(2H, m), 1.4(3H, t),1.3-1.15(4H,                                         437  1.5                                                 37    189       CCl          5 #STR254## Ph 8.9(1H, s), 7.9(1H, d), 7.3-7.1(5H, m), 4.35(1H, m),                         4.1-3.9(3H, m), 3.65(2H, m), 3.35(2H,m), 2.8-2.7(2H,                         m), 1.15(2H, d),0.95(2H, s)                                         485  4.5                                                 25    190       CCl          5 #STR255## tBu                         8.9(1H, s), 7.85(1H, d), 4.3(1H,3.4(2H, m), 2.8(2H,                         m), 1.3(9H,m), 3.95-3.8(3H, m), 3.7(2H, m),s),                         1.2-1.0(4H, m)  465  3  51    191       CH          5 #STR256## H  8.6(1H, s), 7.85(1H, d), 7.2(1H,d), 4.4(1H, m),                         3.9(2H, m), 3.8-3.65(3H, m), 2.9-2.7(2H, m), 1.3(2H,                         d), 1.1(2H, s)  375  2.2                                                 42    192       CH          5 #STR257## Et 8.6(1H, s), 7.8(1H, d), 7.2(1H,d), 4.4(1H, m),                         4.25(2H, q), 3.9-3.7(3H, m), 3.5(2H, m), 2.9-2.7(2H,                         m), 1.3(3H, t), 1.25-0.95(4H, m)                                         403  1.5                                                 40    193       CH          5 #STR258## Ph 8.6(1H, s), 7.8(1H, d), 7.5-7.2(5H, m, 1H, d),                         4.35(1H, m), 4.0-3.8(3H, m), 3.5(2H, m),                         2.85-2.7(2H, m), 1.3(2H, d), 1.15(2H,                                         4.51 4.5                                                 31    194       CH          5 #STR259## tBu                         8.6(1H, s), 7.75(1H, d), 7.2(1H,d), 4.35(1H, m),                         4.0-3.8(3H, m),3.5(2H, m), 2.9-2.7(2H, m), 1.4(9H,                         s), 1.2-1.05(4H, m)                                         431  3  43    195       N          5 #STR260## H  8.6(1H, s), 8.1(1H, d), 4.5(2H,2), 4.3(1H, m),                         3.8.(1H, m), 3.65(1H, m), 3.35(1H, m), 3.0-2.9(2H,                         m), 1.2-1.0(4H, m)                                         376  1  61    196       N          5 #STR261## Et 8.6(1H, s), 8.05(1H, d), 4.55(2H, s), 4.3(1H, m),                         4.25(2H,q), 3.8(1H, m), 3.7(1H, m), 3.4(1H, m),                         3.0-2.85(2H, m), 1.35(3H, t), 1.2-0.95(4H,                                         404  1  57    197       N          5 #STR262## Ph 8.6(1H, s), 8.1(1H, d), 7.7-7.3(5H, m), 4.6(2H, s),                         4.35(1H, m),3.9(1H, m), 3.75(1H, m), 3.4(1H,m),                         3.05-2.8(3H, m), 1.25(2H,d), 1.05(2H,                                         452  1  40    198       N          5 #STR263## tBu                         8.6(1H, s), 8.05(1H, d), 4.55(2H, s), 4.35(1H, m),                         3.95(1H,m), 3.7(1H, m), 3.35(1H, m), 3.0-2.85(2H,                         m), 1.35(9H, s), 1.15(2H, d), 1.0(2H,                                         432  1.5                                                 54    199       N          6 #STR264## H  8.85(1H, s), 8.1(1H, d), 7.751H, m), 7.6(1H, dd),                         7.35(1H,dd), 4.3(1H, m), 3.8(3H, m),3.6(1H, m),                         3.0(1H, m), 2.7(2H, m)                                         448  1  33    200       N          6 #STR265## Et 8.85(1H, s), 8.05(1H, d), 7.75(1H, m), 7.6(1H, dd),                         7.35(1H,dd), 4.3(1H, m), 4.25(2H, q),3.75(3H, m),                         3.6(2H, m), 2.95(2H, m), 2.7-2.6(2H, m), 1.4(3H,                                         476  1  37    201       N          6 #STR266## Ph 8.85(1H, s), 8.1(1H, d), 7.75(1H, m), 7.6(1H, dd),                         7.55-7.35(5H, m, 1H, dd), 4.35(1H, m), 3.75(3H, m),                         3.65(2H, m), 3.0(2H, m),2.85(2H, m)                                         524  1.5                                                 29    202       N          6 #STR267## tBu                         8.85(1H, s), 8.05(1H, d), 7.75(1H, m), 7.55(1H, dd),                         7.3(1H,dd), 4.3(1H, m), 3.8(3H, m), 3.55(2H, m),                         2.9(2H, m), 2.7-2.65(2H, m), 1.3(9H,                                         504  0.5                                                 41    __________________________________________________________________________

EXAMPLE 203 Separation of E, Z Isomer of the Compound Prepared inExample 180 ##STR268##

3.9 g (10 mmol) of the7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid prepared in Example 180 was completely dissolved in 100 ml of asolvent mixture of dichloromethane and methanol (9/1, v/v) under reflux.1.0 g (10.5 mmol) of methanesulfonic acid was added thereto in oneportion while stirring. The resulting solution was heated overnight.After the heated solution was cooled to -10° C., it was filtered. Thefiltrate was twice washed with 10 ml of methanol, then washed with 20 mlof diethylether, and finally dried under nitrogen flow to obtain 3.6 g(Yield 75%) of a beige cake containing oxime Z/E mixture (80:20 onHPLC).

E-isomer: t_(R) =6.64 min

Z-isomer: t_(R) =8.37 min

250 mg of the powder thus obtained was dissolved in 3 ml of water andthe resulting solution was separated on Preparative HPLC. The desiredfraction was collected and readily adjusted to about pH 6.5 by adding 1NNaOH. After the acetonitrile was evaporated, the resulting suspensionwas filtered and washed with water (2 ml×3). The wet cake thus obtainedwas extracted with chloroform (20 ml×2). The remaining solvent wasevaporated and the residue was dried in vacuo to obtain 30 mg of whitesolid. The E- and Z-isomers were collected using the same procedure.

E-isomer

¹ H NMR(CDCl₃, δ, ppm): 8.69(1H,s), 8.05(1H,d,J=12.5 Hz),4.60(2H,dd,J=19 Hz), 4.12(2H,dd,J=8 Hz), 4.00(3H,s), 3.71(1H,m),3.55(1H,m), 3.10(2H,d), 1.36(2H,m), 1.14(2H,m)

Z-isomer(CDCl₃, δ, ppm): 8.70(1H,s), 8.05(1H,d), 4.61(2H,s),4.28(1H,dd), 3.99(3H,s), 3.90(1H,m), 3.69(1H,m), 3.10(1H,m), 3.00(2H,d),1.30(2H), 10.5(2H,m)

EXAMPLE 204 Synthesis of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate

3.89 g (10 mmol) of7-(4-aminomethyl-3-methyloxyminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid prepared as in Example 180 was suspended in 110 ml of a solventmixture of dichloromethane and ethanol (8/2, v/v). 0.94 g (9.8 mmol) ofmethanesulfonic acid was added dropwise thereto and the resultingsolution was thoroughly stirred for 1 hour at 0° C. The solid thusproduced was filtered, washed with ethanol, and then dried to obtain4.55 g of the title compound.

m.p.: 195° C. (dec.); ¹ H NMR(DMSO-d₆) δ (ppm): 8.57(1H,s), 8.02(1H,d)

EXAMPLE 205 Synthesis of7-(4-aminomethyl-3-methyloxyiminorprrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.3 hydrate

A sonicator filled with water was adjusted to 40° C. and was sealed witha lid. Then, a nitrogen introducing tube and a nitrogen excreting tubewere connected to the vessel. When the pressure of the dried nitrogenintroduced through the nitrogen introducing tube was adjusted to 20 psi,the relative humidity of the humidified nitrogen excreted through theexcreting tube was more than 93%. 1 g of the anhydride having moisturecontent of about 2.5% prepared in Example 204 was introduced into afritted filter and the humidified nitrogen prepared according to theabove mentioned process was passed through. Samples were taken after 0,5, 10, 20, 30, and 60 minutes, respectively, and the moisture contentwith the lapse of time was measured. From the results shown in FIG. 8,it can be seen that moisture content of about 10% is constantlymaintained when the humidifying procedure is carried out over 30minutes. The X-ray diffraction pattern of the humidified sample wasidentical to that the 3 hydrate obtained after recrystallization.

EXAMPLE 206 Synthesis of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate.1.5 hydrate

The title compound can be prepared by two different processes.

In the first process, 1.0 g of the anhydride prepared in Example 204 wasdissolved in 17 ml of a mixture of water and acetone (10/7, v/v). Thesolvent was slowly evaporated in darkness leaving 0.8 g of the titlecompound as a solid.

In the second process, 5.0 g of the anhydride prepared in Example 204was added to 10 ml of water and the mixture was heated to about 45° C.in order to dissolve the anhydride. After 20 ml of ethanol was addedthereto, the resulting solution was stirred and then allowed to stand toform a solid. The solid thus produced was filtered and dried undernitrogen flow to obtain 2.6 g of the title compound.

BIOLOGICAL EXAMPLE 1 In vitro Antibacterial Activity Test

The antibacterial activity of the compounds according to the presentinvention was determined by measuring their minimum inhibitoryconcentrations (MIC, μg/ml) against standard strains, clinicallyisolated strains and strains resistant to some antibacterial agents. Inthis test, the known antibacterial compounds, ofloxacin andciprofloxacin, were used as the comparative agents. The minimuminhibitory concentration could be determined by diluting the testcompounds according to a two-times dilution method, dispersing thediluted test compounds in Mueller-Hinton agar medium and theninoculating 5 μl of the standard strain having 10⁷ CFU per ml to themedium, which is then incubated for 18 hours at 37° C. The measuredresults are described in the following Table 25.

                  TABLE 25    ______________________________________    Minimum Inhibitory Concentration of the test compounds (μg/ml)    ______________________________________               Examples    Test Strains 1       12      34    56    89    ______________________________________    Staphylococcus aureus                  ≦0.008                          ≦0.008                                  ≦0.008                                        ≦0.008                                              ≦0.008    6538p    Staphylococcus aureus                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    giorgio    Staphylococcus aureus                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    77    Staphylococcus aureus                 2       1       4     2     1    241    Staphylococcus epider-                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    midis 887E    Staphylococcus epider-                 2       0.5     2     2     0.5    midis 178    Streptococcus faecalis                 0.031   0.031   0.13  0.016 0.063    29212    Bacillus subtilis 6633                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    Micrococcus luteus 9341                 0.063   0.13    0.13  0.063 0.25    Escherichia coli 10536                 ≦0.008                         ≦0.008                                 0.016 ≦0.008                                             0.016    Escherichia coli 3190Y                 ≦0.008                         0.016   ≦0.008                                       ≦0.008                                             0.016    Escherichia coli 851E                 0.016   0.063   0.13  ≦0.008                                             0.063    Escherichia coli TEM3                 0.25    0.5     1     0.5   0.25    3455E    Escherichia coli TEM5                 0.063   0.25    0.5   0.25  0.13    3739E    Escherichia coli TEM9                 0.063   0.25    0.13  0.063 0.063    2639E    Pseudomonas aeruginosa                 1       2       0.5   2     2    1912E    Pseudomonas aeruginosa                 2       0.5     2     2     2    10145    Acinetobacter calco-                 ≦0.008                         0.016   0.031 ≦0.008                                             0.031    aceticus 15473    Citrobacter diversus                 0.063   0.13    0.25  0.016 0.13    2046E    Enterobacter cloacae                 0.031   0.13    0.25  0.031 0.13    1194E    Enterobacter cloacae                 ≦0.008                         0.063   0.063 ≦0.008                                             0.016    P99    Klebsiella aerogenes                 0.25    1       0.5   0.5   0.5    1976E    Klebsiella aerogenes                 0.063   0.13    0.031 0.016 0.25    1082E    Salmonella typimurium                 0.13    0.25    0.063 0.031 0.13    14028    ______________________________________               Examples    Test Strains 97      102     103   104   177    ______________________________________    Staphylococcus aureus                  ≦0.008                          0.016   ≦0.008                                        ≦0.008                                              ≦0.008    6538p    Staphylococcus aureus                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    giorgio    Staphylococcus aureus                 0.016   0.016   ≦0.008                                       ≦0.008                                             0.016    77    Staphylococcus aureus                 2       4       4     8     0.5    241    Staphylococcus epider-                 ≦0.008                         ≦0.008                                 ≦0.008                                       0.016 ≦0.008    midis 887E    Staphylococcus epider-                 1       1       4     4     1    midis 178    Streptococcus faecalis                 0.063   0.063   0.031 0.031 0.031    29212    Bacillus subtilis 6633                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    Micrococcus luteus 9341                 0.063   0.063   0.13  0.13  0.063    Escherichia coli 10536                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    Escherichia coli 3190Y                 ≦0.008                         ≦0.008                                 ≦0.008                                       ≦0.008                                             ≦0.008    Escherichia coli 851E                 0.031   0.063   ≦0.008                                       ≦0.008                                             0.031    Escherichia coli TEM3                 0.13    0.5     0.13  0.25  0.25    3455E    Escherichia coli TEM5                 0.063   0.25    0.063 0.13  0.13    3739E    Escherichia coli TEM9                 0.031   0.063   0.031 0.031 0.063    2639E    Pseudomonas aeruginosa                 1       2       0.5   1     0.5    1912E    Pseudomonas aeruginosa                 1       2       0.5   1     0.5    10145    Acinetobacter calco-                 0.016   0.063   0.031 ≦0.008                                             0.13    aceticus 15473    Citrobacter diversus                 0.063   0.13    0.13  ≦0.008                                             0.031    2046E    Enterobacter cloacae                 0.063   0.25    0.016 ≦0.008                                             0.063    1194E    Enterobacter cloacae                 ≦0.008                         0.031   ≦0.008                                       0.016 0.016    P99    Klebsiella aerogenes                 0.25    0.5     0.063 0.13  0.13    1976E    Klebsiella aerogenes                 0.13    0.25    0.031 0.031 0.063    1082E    Salmonella typimurium                 0.13    0.25    0.031 0.031 0.063    14028    ______________________________________               Examples    Test Strains 178     179     180   OFLX  CFLX    ______________________________________    Staphylococcus aureus                  0.031   ≦0.008                                  ≦0.008                                       0.25   0.13    6538p    Staphylococcus aureus                 0.016   0.016   ≦0.008                                       0.25  0.25    giorgio    Staphylococcus aureus                 0.031   0.031   ≦0.008                                       0.25  0.25    77    Staphylococcus aureus                 1       2       2     64    64    241    Staphylococcus epider-                 0.031   0.016   ≦0.008                                       0.25  0.13    midis 887E    Staphylococcus epider-                 1       2       2     32    128    midis 178    Streptococcus faecalis                 0.063   0.031   0.063 2     0.5    29212    Bacillus subtilis 6633                 0.016   ≦0.008                                 ≦0.008                                       0.063 0.031    Micrococcus luteus 9341                 0.25    0.13    0.13  2     2    Escherichia coli 10536                 0.031   ≦0.008                                 ≦0.008                                       0.031 ≦0.008    Escherichia coli 3190Y                 0.016   ≦0.008                                 ≦0.008                                       0.016 ≦0.008    Escherichia coli 851E                 0.063   ≦0.008                                 ≦0.008                                       0.063 0.016    Escherichia coli TEM3                 1       0.13    0.25  0.5   0.25    3455E    Escherichia coli TEM5                 0.5     0.063   0.13  0.5   0.13    3739E    Escherichia coli TEM9                 0.25    0.031   0.031 0.063 0.031    2639E    Pseudomonas aeruginosa                 0.5     0.25    0.25  0.5   0.31    1912E    Pseudomonas aeruginosa                 1       0.25    0.25  2     0.25    10145    Acinetobacter calco-                 0.13    0.016   0.063 0.25  0.25    aceticus 15473    Citrobacter diversus                 0.13    0.031   0.016 0.063 0.016    2046E    Enterobacter cloacae                 0.13    0.031   0.031 0.063 0.031    1194E    Enterobacter cloacae                 0.063   0.008   ≦0.008                                       ≦0.008                                             ≦0.008    P99    Klebsiella aerogenes                 0.5     0.13    0.13  0.25  0.13    1976E    Klebsiella aerogenes                 0.25    0.031   0.016 0.063 ≦0.008    1082E    Salmonella typimurium                 0.063   0.063   0.031 0.13  0.031    14028    ______________________________________     Note)     OFLX = Ofloxacin     CFLX = Ciprofloxacin

BIOLOGICAL EXAMPLE 2 Pharmacokinetic Test

The pharmacokinteic property parameters of the compounds of the presentinvention were determined using SD rats (male) weighing about 230±10 g.Specifically, the test compounds of the present invention wereadministered in an amount of 20 mg/kg of body weight to test rats viafemoral veins. Then, bloods were collected at certain intervals afteradministration of the test compounds from femoral veins and analyzed bymeans of Agar Well Method to measure the blood concentration of the testcompounds from which pharmacokinetic parameters, half life (T_(1/2)) andAUC (area under the curve) were calculated. The obtained results aredescribed in the following Table 26.

                  TABLE 26    ______________________________________    Pharmacokinetic parameters              T.sub.1/2  C.sub.max  T.sub.max                                            F    Route     (hr)       (μg/ml) (hr)    (%)    ______________________________________    CFLX  IV      1.76 ± 0.035              71          PO       1.7 ± 0.108                             1.34 ± 0.368                                      1.13 ± 0.605    EX. 89          IV      2.29 ± 1.13              >100          PO      6.69 ± 2.78                             4.89 ± 2.23                                      2.18 ± 0.77    EX. 177          IV      1.92 ± 0.38              47.23          PO      3.93 ± 1.31                             0.37 ± 0.11                                      0.51 ± 0.33    ______________________________________     Note:     CFLX = Ciprofloxacin     IV = Intravenous     PO = Per oral     T.sub.1/2 = Biological half life     C.sub.max = Maximum blood concentration     T.sub.max = Time showing maximum blood concentration after administration     of the test compound     F = Bioavailability

BIOLOGICAL EXAMPLE 3 Acute Oral Toxicity Test

To determine the acute oral toxicity of the compounds prepared inExamples 1 and 34, the test solution containing the compounds in variousconcentrations were orally administered to ICR male mouse in an amountof 10 ml per kg of body weight. For 7 days after administration, thelethality and the conditions of test mouse were observed, from whichLD₅₀ value (mg/kg) was calculated. The obtained results are described inthe following Table 27.

                  TABLE 27    ______________________________________    Toxicity    Test Compound   LD.sub.50  value    (Example No.)   (mg/kg)    ______________________________________    1               >3,000    34              >3,000    ______________________________________

TEST EXAMPLE 1 Moisture Adsorption Test of the Anhydride Prepared inExample 204

Under various relative humidities at 25° C., the moisture adsorptionvelocity and the equilibrium moisture content of the anhydride preparedin Example 203 were determined by means of an automatic moistureadsorption analyzer (MB 300 G Gravimetric Sorption Analyzer). Thisinstrument produces a specific relative humidity at a specifictemperature and continuously records the weight change of a sample dueto adsorption or desorption of moisture as measured by a micro balanceinside the instrument. 16 mg of the anhydride sample was loaded on themicro balance and the moisture contained in the sample was removed undera dry nitrogen stream at 50° C. A weight change of less than 5 μg per 5minutes was the criterion for complete dryness. Thereafter, the innertemperature was adjusted to 25° C., and the sample was tested varyingthe relative humidity from 0 to 95% at 5% intervals. The sample wasconsidered to have reached equilibrium at each relative humidity testedwhen the weight change was less than 5 μg per 5 minutes. FIG. 1 showsthe moisture adsorption velocity, that is, the time required for thesample to reach equilibrium at each relative humidity from 0 to 95% at5% intervals. Initial moisture adsorption proceeded very speedily ateach relative humidity tested. In most cases, the equilibrium wasreached within 2 hours. FIG. 2 shows the weight increment(%) at eachrelative humidity, that is, the equilibrium moisture content. It isclear from FIG. 2 that the equilibrium moisture content is dependentupon the relative humidity.

TEST EXAMPLE 2 Thermal Analysis of the Anhydride Prepared in Example 204and 3 Hydrate Prepared in Example 205

For the Differential Scanning Calorimetry, METTLER TOLEDO DSC821e andMETTLER TOLEDO STARe System were used. 3.7 mg of sample was weighed intothe aluminum pan, which was then press sealed with an aluminum lid.After three tiny needle holes were made on the lid, the sample wastested by heating from normal temperature to 250° C. at a rate of 10°C./min. As can be seen from FIG. 9, the endothermic peak due to thevaporization of the water molecules contained in the 3 hydrate begins ataround 50° C. and the exothermic peak due to the thermal decompositionwas observed at around 180 to 220° C. In contrast, the anhydride showedonly an exothermic peak due to thermal decomposition at around 185 to220° C. without any endothermic peak.

In the thermogravimetric analysis, SEIKO TG/DTA220 was used. 3.8 mg ofthe sample was weighed into an aluminum pan and was heated from normaltemperature to 250° C. at a rate of 10° C./min according to thetemperature raising program. As can be seen from FIG. 10, weightdecrement was observed at the temperature range of endothermic peak, theextent of which corresponds to the moisture content determined byKarl-Fisher method (Mettler Toledo DL37KF Coulometer).

TEST EXAMPLE 3 Equilibrium Moisture Content Determination of Hydrates

Six saturated aqueous salt solutions were introduced into eachdesiccator to control the inner relative humidity to a specific value asrepresented in the following Table 28. Then, equilibrium moisturecontents of 3 hydrate and 1.5 hydrate prepared in Examples 205 and 206,respectively, were determined at several relative humidities.

                  TABLE 28    ______________________________________    Saturated salt solutions inside the desiccator    Salt Solution Relative Humidity(%) at 25° C.    ______________________________________    Potassium Acetate                  23    Magnesium Chloride                  33    Potassium Carbonate                  43    Magnesium Nitrate                  52    Sodium Nitrite                  64    Sodium Chloride                  75    ______________________________________

Specifically, 100 mg of the sample was spread on a pre-weighed Petridish and the total weight was accurately measured, then three of thesample were placed in each desiccator of Table 28. The desiccators wereallowed to stand at normal temperature for 7 days and then the samplewas taken to be weighed. After 13 days had passed, one of the threesamples inside each desiccator was taken and the moisture content ofeach was measured by the thermogravimetric analysis described in TestExample 2. Equilibrium moisture content at each relative humidity isrepresented in FIG. 3 (3 hydrate) and FIG. 4 (1.5 hydrate). FIG. 3 showsthat moisture content of the 3 hydrate is maintained around 10% for thewhole relative humidity range tested; FIG. 4 shows that the moisturecontent of the 1.5 hydrate is maintained around 5% at the relativehumidity of 23 to 64%. Both hydrates are stable since they keep aconstant equilibrium moisture content regardless of the relativehumidity change.

TEST EXAMPLE 4 X-ray Diffraction Analysis

After 50 mg of the anhydride in Example 204, the 3 hydrate in Example205, and the 1.5 hydrate in Example 206 were each thinly spread on thesample holder, X-ray diffraction analyses (35 kV×20 mA Rigaku GergeflexD/max-IIIC) were performed under the conditions listed below.

scan speed (2θ) 5°/min

sampling time: 0.03 sec

scan mode: continuous

2θ/θ reflection

Cu-target (Ni filter)

Results of X-ray diffraction analyses on the anhydride, the 3 hydrate,and the 1.5 hydrate were as depicted in FIG. 5, 6, and 7, respectively.From these spectra it can be verified that their crystal forms differfrom each other.

TEST EXAMPLE 5 Chemical Stability Under Heating

The chemical stability of both the 3 hydrate prepared in Example 205 andthe 1.5 hydrate prepared in Example 206 were compared with the chemicalstability of the anhydride prepared in Example 204 as follows in orderto determine the effect on chemical stability of the extent ofhydration.

The anhydride and each of the hydrates was introduced into a glass vialand maintained at 70° C. Then, the extent of decomposition with elapsedtime was analyzed by liquid chromatography and the results thus obtainedare described in the following Table 29.

                  TABLE 29    ______________________________________    Thermal stability with elapsed time (at 70° C.)            Time(week)            (Unit: %)    Sample    Initial   1      2       3    4    ______________________________________    Anhydrate 99        --     97      --   95    3 hydrate 97        --     --      --   94    1.5 hydrate              100       97.25  95.80   97.16                                            96.17    ______________________________________

As can be from Table 29, the 3 hydrate and the 1.5 hydrate both showedthe same degree of thermal stability as the anhydride.

TEST EXAMPLE 6 Water Solubility of the Compound Prepared in Example 204

Water solubilities of various salts of the compound, including that ofthe methanesulfonate prepared in Example 204, were measured. Themeasurement results are listed in the following Table 30.

                  TABLE 30    ______________________________________    Water Solubility                 Phosphate buffered                              Phosphate buffered    Sample       solution (pH7)                              solution (pH2)    ______________________________________    Free form    0.007        14.6    Tartarate    6.7          15.4    Sulfurate    11.4         8.9    p-Toluenesulfonate                 7.5          6.8    Methanesulfonate                 >30          >20    ______________________________________

As can be seen from the above results, the methanesulfonate shows awater solubility superior to that of the tartarate, the sulfurate, andthe p-toluenesulfonate as well as the free form. Therefore, it isidentified that the methanesulfonate has a desirable solubility as wellas an excellent antibacterial activity.

BIOLOGICAL EXAMPLE 4 In vitro Antibacterial Activity Test

In order to determine the antibacterial activitiers of the E- andZ-isomer of the compound 180 which were separated in Example 203, and of7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate prepared in Example 204, in vitro antibacterialactivities of them were measured using agar medium dilution method. Theresults were as described in the following Tables 31 and 32. In Table32, the minimum inhibitory concentration (MIC, μg/ml) was simplycalculated in the ratio of weight without considering the molecularweight, and ciprofloxacin was chosen as the control. From the results,it is identified that the Z-isomer has a superior antibacterial activityto the E-isomer and that the methanesulfonate as well as the free formhas an excellent antibacterial activity.

                  TABLE 31    ______________________________________    In vitro Antibacterial activity (Minimum Inhibitory Concentration:    MIC, μg/ml)                                        Cipro-    Test Strains      E-isomer Z-isomer floxacin    ______________________________________    Staphylococcus aureus 6538p                      0.063    ≦0.008                                        0.13    Staphylococcus aureus giorgio                      0.063    ≦0.008                                        0.13    Staphylococcus aureus 77                      0.063    0.031    0.25    Staphylococcus aureus 241                      16       4        64    Staphylococcus epidermidis 887E                      0.031    ≦0.008                                        0.063    Staphylococcus epidermidis 178                      32       4        128    Streptococcus faecalis 29212                      0.25     0.063    1    Bacillus subtilis 6633                      0.031    ≦0.008                                        0.031    Micrococcus luteus 9341                      0.5      0.13     2    Escherichia coli 10536                      0.031    ≦0.008                                        0.016    Escherichia coli 3190Y                      0.016    ≦0.008                                        ≦0.008    Escherichia coli 851E                      0.063    0.016    ≦0.008    Escherichia coli TEM3 3455E                      0.5      0.13     0.25    Escherichia coli TEM5 3739E                      0.5      0.13     0.13    Escherichia coli TEM9 2639E                      0.13     0.031    0.016    Pseudomonas aeruginosa 1912E                      1        0.5      0.25    Pseudomonas aeruginosa 10145                      2        0.5      0.25    Pseudomonas aeruginosa 6065Y                      32       8        4    Acinetobacter calcoaceticus 15473                      0.25     0.063    0.25    Citrobacter diversus 2046E                      0.13     0.031    0.031    Enterobacter cloacae 1194E                      0.13     0.031    0.016    Enterobacter cloacae P99                      0.031    ≦0.008                                        ≦0.008    Klebsiella aerogenes 1976E                      0.25     0.063    0.13    Klebsiella aerogenes 1082E                      0.13     0.031    0.016    Proteus vulgaris 6059                      1        0.25     0.031    Seratia marsecence 1826E                      0.5      0.25     0.063    Salmonella thypimurium 14028                      0.13     0.031    0.031    ______________________________________

                  TABLE 32    ______________________________________    In vitro Antibacterial activity (Minimum Inhibitory    Concentration: MIC, μg/ml)                      Methanesulfonic    Test Strains      acid salt   Ciprofloxacin    ______________________________________    Staphylococcus aureus 6538p                      0.016       0.13    Staphylococcus aureus giorgio                      0.016       0.13    Staphylococcus aureus 77                      0.031       0.25    Staphylococcus aureus 241                      4           128    Staphylococcus epidermidis 887E                      0.016       0.013    Staphylococcus epidermidis 178                      4           128    Streptococcus faecalis 29212                      0.13        0.5    Bacillus subtilis 6633                      0.016       0.031    Micrococcus luteus 9341                      0.13        2    Escherichia coli 10536                      0.008       <0.008    Escherichia coli 3190Y                      0.008       <0.008    Escherichia coli 851E                      0.016       <0.008    Escherichia coli TEM3 3455E                      0.25        0.5    Escherichia coli TEM5 3739E                      0.13        0.13    Escherichia coli TEM9 2639E                      0.031       0.016    Pseudomonas aeruginosa 1912E                      0.25        0.13    Pseudomonas aeruginosa 10145                      0.5         0.5    Acinetobacter calcoaceticus 15473                      0.031       0.25    Citrobacter diversus 2046E                      0.031       0.016    Enterobacter cloacae 1194E                      0.031       0.016    Enterobacter cloacae P99                      0.016       <0.008    Klebsiella aerogenes 1976E                      0.13        0.13    Klebsiella aerogenes 1082E                      0.031       0.016    Proteus vulgaris 6059                      0.25        0.031    Seratia marsecence 1826E                      0.13        0.063    Salmonella thypimurium 14028                      0.031       0.031    ______________________________________

Although this invention has been described in its preferred form with acertain degree of particularity, it is appreciated by those skilled inthe art that the present disclosure of the preferred form has been madeonly by way of example and that numerous changes in the details of theconstruction, combination and arrangement of parts may be resorted towithout departing from the spirit and scope of the invention.

What is claimed is:
 1. A method for prophylaxis or treatment ofbacterial infections in a warm blooded animal, comprising administeringan effective amount of the compound7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid of the following formula: ##STR269## or a pharmaceuticallyacceptable non-toxic salt, physiologically hydrolyzable ester, or isomerthereof.
 2. The method according to claim 1 wherein the compound is inthe form of Z-isomer.
 3. The method according to claim 1 wherein thecompound is administered once a day.
 4. The method according to claim 1wherein the warm blooded mammal is a human being.
 5. A method forprophylaxis or treatment of bacterial infections in a warm bloodedanimal, comprising administering7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate or a hydrate thereof of the following formula:##STR270## in which n is 0, 1, 1.5, 2.5, 3, 3.5 or 4, or an isomerthereof.
 6. The method according to claim 5 wherein the compound is inthe form of Z-isomer.
 7. The method according to claim 5 wherein n is 3.8. The method according to claim 5 wherein the compound has a moisturecontent of from 9 to 11% by weight.
 9. The method according to claim 5wherein n is 1.5.
 10. The method according to claim 5 wherein thecompound has a moisture content of from 4 to 6% by weight.
 11. Themethod according to claim 5 wherein the compound is administered once aday.
 12. The method according to claim 5 wherein the warm blooded animalis a human being.